167 results on '"Michael C. Archer"'
Search Results
2. Data from mda-7/IL-24 Expression Inhibits Breast Cancer through Upregulation of Growth Arrest-Specific Gene 3 (gas3) and Disruption of β1 Integrin Function
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Yaacov Ben-David, Michael C. Archer, Paul B. Fisher, Rupesh Dash, Qi Li, Burton B. Yang, Sze W. Shan, Eldad Zacksenhaus, Jeff C. Liu, Laura M. Vecchiarelli-Federico, Yanmei Li, Guodong Liu, and You-Jun Li
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Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of β1 integrin with fibronectin. A mutated GAS3, which is unable to bind β1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of β1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of β1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P = 1.02 × 10−9), and the incidence of metastases is significantly reduced in patients with HER2+ breast cancer expressing high-levels of IL-20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-β1integrin–fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy. Mol Cancer Res; 11(6); 593–603. ©2013 AACR.
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- 2023
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3. The interplay between cell signalling and the mevalonate pathway in cancer
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Peter J. Mullen, Rosemary Yu, Michael C. Archer, Joseph Longo, and Linda Z. Penn
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0301 basic medicine ,Cell signaling ,animal structures ,viruses ,General Mathematics ,Mevalonic Acid ,Biology ,complex mixtures ,03 medical and health sciences ,Neoplasms ,medicine ,Humans ,Applied Mathematics ,Cancer ,hemic and immune systems ,Metabolism ,medicine.disease ,Cell biology ,Metabolic pathway ,030104 developmental biology ,Cancer metabolism ,Mevalonate pathway ,Signal transduction ,Signalling pathways ,Metabolic Networks and Pathways ,Signal Transduction - Abstract
The mevalonate (MVA) pathway is an essential metabolic pathway that uses acetyl-CoA to produce sterols and isoprenoids that are integral to tumour growth and progression. In recent years, many oncogenic signalling pathways have been shown to increase the activity and/or the expression of MVA pathway enzymes. This Review summarizes recent advances and discusses unique opportunities for immediately targeting this metabolic vulnerability in cancer with agents that have been approved for other therapeutic uses, such as the statin family of drugs, to improve outcomes for cancer patients.
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- 2016
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4. Risk factors for colorectal cancer in man induce aberrant crypt foci in rats: Preliminary findings
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HoYin Lip, W. Robert Bruce, Sara Fard, A. Pietro Femia, Alan Medline, Adria Giacca, Kai Yang, Kate Banks, Michael C. Archer, Wendy E. Ward, Rudolf Furrer, Giovanna Caderni, Peter J. O'Brien, and Rhea Mehta
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0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Colon ,Medicine (miscellaneous) ,Physiology ,chemistry.chemical_element ,Calcium ,Gastroenterology ,digestive system ,Article ,03 medical and health sciences ,0302 clinical medicine ,Environmental risk ,Aberrant Crypt Foci ,Risk Factors ,Internal medicine ,Vitamin D and neurology ,Medicine ,Animals ,Humans ,Carcinogen ,Calcium metabolism ,Nutrition and Dietetics ,business.industry ,Original Articles ,medicine.disease ,digestive system diseases ,Rats, Inbred F344 ,Rats ,Disease Models, Animal ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,business ,Colorectal Neoplasms ,Human colon ,Aberrant crypt foci - Abstract
Epidemiological studies have demonstrated clear associations between specific dietary and environmental risk factors and incidence of colorectal cancer, but the mechanisms responsible for these associations are not known. An animal model could facilitate such an understanding. Both genotoxic and nongenotoxic carcinogens induce aberrant crypt foci (ACF) in the colons of F344 rats. F344 rats were provided with diets that contained putative risk factors for CRC: low calcium and low vitamin D, high iron, high fructose, and decreased light (UV) exposure or a control diet for 14 wk. The rats were then assessed with biochemical measures and by topological examination for evidence of colon abnormalities. Circulating ionized calcium was decreased from 2.85 to 1.69 mmol/L, and ACF were increased from 0.7 to 13.6 lesions/colon (both P < 0.001). Rats exposed to the multiple environmental conditions associated with colon cancer, developed ACF similar to the heterogeneous or ill-defined ACF in the human colon. Heterogeneous ACF are the most frequently seen in humans and are also seen in rats shortly after exposure to the non-genotoxic colon carcinogen, dextransulfate sodium. The rodent model could be used to assess the pathways from diet and environment to colon cancer and to provide guidance for clinical studies.
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- 2015
5. MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer
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Xiang-Yang Wang, Michael C. Archer, Mark A. Subler, Swadesh K. Das, Paul B. Fisher, You-Jun Li, Mitchell E. Menezes, Fang Yuan, Xue-Ning Shen, Luni Emdad, Eldad Zacksenhaus, Yaacov Ben-David, Devanand Sarkar, Chunqing Guo, and Jolene J. Windle
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Genetically modified mouse ,Tumor suppressor gene ,Receptor, ErbB-2 ,Cellular differentiation ,Apoptosis ,Mammary Neoplasms, Animal ,Mice, Transgenic ,transgenic mice ,Transgenic Model ,Immunoenzyme Techniques ,Mice ,Breast cancer ,Pregnancy ,In vivo ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,skin and connective tissue diseases ,melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) ,Mammary tumor ,business.industry ,Interleukins ,Melanoma ,Cell Differentiation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MMTV-MDA-7 mice ,Disease Models, Animal ,Cell Transformation, Neoplastic ,Mammary Tumor Virus, Mouse ,Oncology ,Immunology ,Cancer research ,MMTV-PyMT mice ,Female ,business ,MMTV-MDA-7/MMTV-Erbb2 mice ,Priority Research Paper - Abstract
Melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24) is a novel member of the IL-10 gene family that selectively induces apoptosis and toxic autophagy in a broad spectrum of human cancers, including breast cancer, without harming normal cells or tissues. The ability to investigate the critical events underlying cancer initiation and progression, as well as the capacity to test the efficacy of novel therapeutics, has been significantly advanced by the development of genetically engineered mice (GEMs) that accurately recapitulate specific human cancers. We utilized three transgenic mouse models to better comprehend the in vivo role of MDA-7/IL-24 in breast cancer. Using the MMTV-PyMT spontaneous mammary tumor model, we confirmed that exogenously introducing MDA-7/IL-24 using a Cancer Terminator Virus caused a reduction in tumor burden and also produced an antitumor "bystander" effect. Next we performed xenograft studies in a newly created MMTV-MDA-7 transgenic model that over-expresses MDA-7/IL-24 in the mammary glands during pregnancy and lactation, and found that MDA-7/IL-24 overexpression delayed tumor growth following orthotopic injection of a murine PDX tumor cell line (mPDX) derived from a tumor formed in an MMTV-PyMT mouse. We also crossed the MMTV-MDA-7 line to MMTV-Erbb2 transgenic mice and found that MDA-7/IL-24 overexpression delayed the onset of mammary tumor development in this model of spontaneous mammary tumorigenesis as well. Finally, we assessed the role of MDA-7/IL-24 in immune regulation, which can potentially contribute to tumor suppression in vivo. Our findings provide further direct in vivo evidence for the role of MDA-7/IL-24 in tumor suppression in breast cancer in immune-competent transgenic mice.
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- 2015
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6. Suppression of Her2/Neu mammary tumor development in mda-7/IL-24 transgenic mice
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Lei Xia, Michael C. Archer, Yaacov Ben-David, Paul B. Fisher, Luni Emdad, Guodong Liu, You-Jun Li, Mitchell E. Menezes, Swadesh K. Das, Xiao Xiao, Eldad Zacksenhaus, Devanand Sarkar, and Jeff C. Liu
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Genetically modified mouse ,Pathology ,medicine.medical_specialty ,Tumor suppressor gene ,Receptor, ErbB-2 ,mouse model ,Apoptosis ,Mammary Neoplasms, Animal ,Mice, Transgenic ,Real-Time Polymerase Chain Reaction ,HER2/neu ,Immunoenzyme Techniques ,Mice ,breast cancer ,mda-7/IL-24 ,prevention ,HER2 ,Animals ,Humans ,Medicine ,RNA, Messenger ,skin and connective tissue diseases ,Mammary tumor ,Tumor microenvironment ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Interleukins ,Melanoma ,Membrane Proteins ,Cancer ,medicine.disease ,Molecular medicine ,Rats ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Cell Transformation, Neoplastic ,Mammary Tumor Virus, Mouse ,Oncology ,biology.protein ,Cancer research ,Female ,business ,Priority Research Paper - Abstract
// You-Jun Li 1,* , Guodong Liu 2,* , Lei Xia 4 , Xiao Xiao 4 , Jeff C. Liu 5 , Mitchell E. Menezes 6 , Swadesh K. Das 6 , Luni Emdad 6 , Devanand Sarkar 6 , Paul B. Fisher 6 , Michael C. Archer 2,3 , Eldad Zacksenhaus 3,5 and Yaacov Ben-David 3,4 1 Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin, China 2 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada 3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 4 Division of Biology, The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China 5 Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada 6 Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA * These authors have contributed equally to this work Correspondence to: Yaacov Ben-David, email: // Eldad Zacksenhaus, email: // Keywords : mda-7/IL-24, HER2, breast cancer, prevention, mouse model Received : July 06, 2015 Accepted : September 23, 2015 Published : October 09, 2015 Abstract Melanoma differentiation associated gene-7/interleukin-24 ( mda-7/IL-24 ) encodes a tumor suppressor gene implicated in the growth of various tumor types including breast cancer. We previously demonstrated that recombinant adenovirus-mediated mda-7/IL-24 expression in the mammary glands of carcinogen-treated (methylnitrosourea, MNU) rats suppressed mammary tumor development. Since most MNU-induced tumors in rats contain activating mutations in Ha-ras, which arenot frequently detected in humans, we presently examined the effect of MDA-7/IL-24 on Her2/Neu - induced mammary tumors, in which the RAS pathway is induced. We generated tet-inducible MDA-7/IL-24 transgenic mice and crossed them with Her2/Neu transgenic mice. Triple compound transgenic mice treated with doxycycline exhibited a strong inhibition of tumor development, demonstrating tumor suppressor activity by MDA-7/IL-24 in immune-competent mice. MDA-7/IL-24 induction also inhibited growth of tumors generated following injection of Her2/Neu tumor cells isolated from triple compound transgenic mice that had not been treated with doxycycline, into the mammary fat pads of isogenic FVB mice. Despite initial growth suppression, tumors in triple compound transgenic mice lost mda-7/IL-24 expression and grew, albeit after longer latency, indicating that continuous presence of this cytokine within tumor microenvironment is crucial to sustain tumor inhibitory activity. Mechanistically, MDA-7/IL-24 exerted its tumor suppression effect on HER2 + breast cancer cells, at least in part, through PERP, a member of PMP-22 family with growth arrest and apoptosis-inducing capacity. Overall, our results establish mda-7/IL-24 as a suppressor of mammary tumor development and provide a rationale for using this cytokine in the prevention/treatment of human breast cancer.
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- 2015
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7. Role of Sp Transcription Factors in the Regulation of Cancer Cell Metabolism
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Michael C. Archer
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Cancer Research ,Hexokinase ,Akt/PKB signaling pathway ,Reviews ,Promoter ,Biology ,chemistry.chemical_compound ,Biochemistry ,chemistry ,Lipogenesis ,Genetics ,Glycolysis ,Transcription factor ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
Cancer cells exhibit altered metabolism characterized by the generation of adenosine triphosphate by glycolysis and generation of fatty acids by de novo synthesis. The majority of genes involved in these pathways have binding sites for specificity protein (Sp) transcription factors in their promoters. Studies showing that Sp transcription factors, particularly Sp1, are involved in the regulation in cancer cells of hexokinase, pyruvate kinase, lactate dehydrogenase, fatty acid synthase, and hypoxia-inducible factor-1α are reviewed. Glycolysis and lipogenesis in cancers are also known to be stimulated by the constitutive activation of the PI3K/Akt signaling pathway. Evidence is presented for the notion that Sp transcription factors may act in concert with Akt to regulate the abnormal metabolism of cancer cells.
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- 2011
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8. Diabetes and Cancer: A Consensus Report
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Michael Pollak, Edward Giovannucci, Susan M. Gapstur, Judith G. Regensteiner, David M. Harlan, Richard M. Bergenstal, Douglas Yee, Michael C. Archer, and Laurel A. Habel
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medicine.medical_specialty ,Diabetes risk ,Alcohol Drinking ,MEDLINE ,Motor Activity ,Overweight ,Incretins ,Body Mass Index ,Receptor, IGF Type 1 ,Diabetes Complications ,Sex Factors ,Risk Factors ,Hyperinsulinism ,Neoplasms ,Internal medicine ,Diabetes mellitus ,Epidemiology of cancer ,Diabetes Mellitus ,medicine ,Humans ,Hypoglycemic Agents ,Insulin ,Testosterone ,Intensive care medicine ,American diabetes association ,business.industry ,Racial Groups ,Smoking ,Age Factors ,Cancer ,Estrogens ,Hematology ,medicine.disease ,Metformin ,Receptor, Insulin ,Diet ,Sulfonylurea Compounds ,Endocrinology ,Oncology ,Hyperglycemia ,Cytokines ,Thiazolidinediones ,medicine.symptom ,business ,Body mass index - Abstract
Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetes risk factors and treatments. This consensus statement of experts assembled jointly by the American Diabetes Association and the American Cancer Society reviews the state of science concerning 1) the association between diabetes and cancer incidence or prognosis; 2) risk factors common to both diabetes and cancer; 3) possible biologic links between diabetes and cancer risk; and 4) whether diabetes treatments influence the risk of cancer or cancer prognosis. In addition, key unanswered questions for future research are posed.
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- 2010
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9. Diabetes and Cancer
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Edward Giovannucci, Judith G. Regensteiner, Douglas Yee, Susan M. Gapstur, Michael C. Archer, Michael Pollak, Laurel A. Habel, David M. Harlan, and Richard M. Bergenstal
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medicine.medical_specialty ,Pathology ,Diabetes risk ,Endocrinology, Diabetes and Metabolism ,Consensus Report ,Cancer prognosis ,Risk Factors ,Diabetes mellitus ,Neoplasms ,Epidemiology of cancer ,Internal Medicine ,Diabetes Mellitus ,Medicine ,Humans ,Hypoglycemic Agents ,Intensive care medicine ,Preventive healthcare ,Advanced and Specialized Nursing ,American diabetes association ,business.industry ,Reviews/Commentaries/ADA Statements ,Incidence ,Cancer ,medicine.disease ,Prognosis ,Cancer incidence ,business - Abstract
Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetes risk factors and diabetes treatments. This consensus statement of experts assembled jointly by the American Diabetes Association and the American Cancer Society reviews the state of science concerning 1) the association between diabetes and cancer incidence or prognosis, 2) risk factors common to both diabetes and cancer, 3) possible biologic links between diabetes and cancer risk, and 4) whether diabetes treatments influence risk of cancer or cancer prognosis. In addition, key unanswered questions for future research are posed.
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- 2010
10. Elevated circulating adiponectin and elevated insulin sensitivity in adiponectin transgenic mice are not associated with reduced susceptibility to colon carcinogenesis
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Michael C. Archer and Kafi N. Ealey
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Male ,Cancer Research ,medicine.medical_specialty ,Colon ,Colorectal cancer ,medicine.medical_treatment ,Azoxymethane ,Adipokine ,Mice, Transgenic ,Weight Gain ,Mice ,chemistry.chemical_compound ,Insulin resistance ,Internal medicine ,medicine ,Hyperinsulinemia ,Animals ,Humans ,Insulin ,Insulin-Like Growth Factor I ,Cells, Cultured ,Pancreatic hormone ,Adiponectin ,business.industry ,Glucose Tolerance Test ,medicine.disease ,Endocrinology ,Oncology ,chemistry ,Colonic Neoplasms ,Carcinogens ,Female ,Disease Susceptibility ,Insulin Resistance ,business ,Precancerous Conditions - Abstract
Obesity, particularly visceral adiposity, is an established risk factor for colorectal cancer (CRC) and this is thought to result, at least in part, from insulin resistance and chronic hyperinsulinemia that may be mediated by adipokines. Serum levels of adiponectin, the most abundant protein secreted from adipocytes, are decreased in obesity and are inversely associated with insulin resistance and hyperinsulinemia. The objective of this study was to determine whether elevated circulating adiponectin plays a role in colon carcinogenesis using adiponectin transgenic (AdTg) mice that have 2–3-fold elevated circulating adiponectin but similar body weights as wildtype (WT) littermates used as controls. Eight-week old male and female AdTg and WT mice were treated with 4 weekly injections of the colon-specific carcinogen azoxymethane (AOM). One week following the last dose of AOM, all mice were placed on a high-fat diet and killed 24 weeks later, at 36 weeks of age, for the analysis of colon tumors. Glucose tolerance tests (GTT) were performed by injecting 2g/kg dextrose or 1.25–1.5 g/kg dextrose into all 12-week and 32–35-week-old mice respectively, and measuring blood from the tail vein 15, 30, 60 and 120 min following glucose administration. There were no significant differences in colon tumor incidence, number or size between AdTg and WT mice of either sex. AdTg mice of both sexes displayed resistance to diet-induced decreases in insulin sensitivity. Our results show that constitutively elevated levels of circulating adiponectin in AdTg mice do not confer protection against the development of colon tumors. © 2008 Wiley-Liss, Inc.
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- 2009
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11. Interleukin-24 Induces Expression of β4 Integrin but Suppresses Anchorage-Independent Growth of Rat Mammary Tumor Cells by a Mechanism That Is Independent of β4
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Michael C. Archer, Yaacov Ben-David, You-Jun Li, Wanli Xuan, and Guodong Liu
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STAT3 Transcription Factor ,Cancer Research ,Gene Expression ,Mice, Nude ,Rats, Inbred WF ,Apoptosis ,Cell Growth Processes ,Adenocarcinoma ,Mice ,Cell Movement ,In vivo ,Cell Line, Tumor ,Interleukin 24 ,Animals ,STAT3 ,Molecular Biology ,Mammary tumor ,biology ,Microarray analysis techniques ,Interleukins ,Integrin beta4 ,Mammary Neoplasms, Experimental ,Microarray Analysis ,Rats ,Up-Regulation ,Oncology ,Cell culture ,Cancer research ,biology.protein ,Ectopic expression ,Anchorage-Independent Growth ,Cyclin-Dependent Kinase Inhibitor p27 - Abstract
Wistar-Furth rats develop multiple mammary adenocarcinomas following initiation with methylnitrosourea, whereas Copenhagen rats are resistant to the development of mammary tumors. We have previously isolated cell lines from tumors induced in resistant Copenhagen × Wistar-Furth F1 rats by infusion of a retrovirus harboring v-Ha-ras directly into the main mammary ducts. Some of the cell lines were able to grow in soft agar, but a significant number did not display anchorage-independent growth. Here, we compared by microarray analysis genes that are differentially expressed in these cell lines. The expression of interleukin-24 (IL-24) and β4 integrin was highly correlated with the inability of cells to grow in soft agar. Ectopic expression of IL-24 in anchorage-independent cells inhibited their growth in monolayer culture, in soft agar, and in nude mice in vivo and inhibited their ability to migrate and invade in in vitro assays. Furthermore, growth suppression by IL-24 was associated with the transcriptional up-regulation of p27Kip1 via the activation of Stat3. We showed, for the first time, that β4 integrin is a downstream target of IL-24. However, β4 does not play a direct role in regulating the proliferative capacity of rat mammary tumor cells. Our results show that IL-24 suppresses the growth of rat mammary carcinoma cells and may play a role in the resistance of Copenhagen rats to mammary carcinogenesis. (Mol Cancer Res 2009;7(3):433–42)
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- 2009
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12. Induction of Hepatic Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) in Rats by Dietary n-6 Polyunsaturated Fatty Acids
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Amit K. Ghoshal, Zhaoming Xu, Geoffrey A. Wood, and Michael C. Archer
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General Biochemistry, Genetics and Molecular Biology - Published
- 2008
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13. Farnesol Decreases Serum Triglycerides in Rats: Identification of Mechanisms Including Up-Regulation of PPARα and Down-Regulation of Fatty Acid Synthase in Hepatocytes
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Michael C. Archer and Robin E. Duncan
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Male ,medicine.medical_specialty ,Down-Regulation ,Tretinoin ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,PPAR alpha ,RNA, Messenger ,Carnitine ,Alitretinoin ,Cells, Cultured ,Triglycerides ,Retinoid X Receptor beta ,chemistry.chemical_classification ,Carnitine O-Palmitoyltransferase ,biology ,Triglyceride ,Organic Chemistry ,Hypertriglyceridemia ,Fatty acid ,Cell Biology ,Farnesol ,medicine.disease ,Rats ,Up-Regulation ,Fatty acid synthase ,Endocrinology ,chemistry ,Lipogenesis ,Hepatocytes ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Acyl-CoA Oxidase ,Peroxisome proliferator-activated receptor alpha ,Fatty Acid Synthases ,medicine.drug - Abstract
Obesity is associated with impaired fatty acid (FA) oxidation and increased de novo hepatic lipogenesis that may contribute to the development of hypertriglyceridemia, an important risk factor for the development of cardiovascular disease. Strategies to improve hepatocyte FA metabolism, including dietary interventions, are therefore important for the prevention of obesity-associated co-morbidities. Farnesol is consumed in the diet as a component of plant products. In the present study, we administered farnesol orally to rats for seven days and found significantly reduced serum triglyceride concentrations compared with controls. Potential mechanisms underlying the hypotriglyceridemic effect of farnesol were investigated using clone-9 cultured rat hepatocytes. Farnesol significantly upregulated expression of peroxisome proliferator-activated receptor alpha (PPARalpha) and the PPARalpha-regulated genes fatty acyl-CoA oxidase and carnitine palmitoyl transferase 1a, suggesting that increased hepatic FA oxidation may contribute to serum triglyceride lowering in rats. Farnesol did not change SREBP-1c mRNA levels, but significantly down-regulated fatty acid synthase (FAS) mRNA and protein levels and activity, indicating that attenuated lipogenesis may also contribute to hypotriglyceridemic effects of farnesol in vivo. Rescue experiments revealed that down-regulation of FAS by farnesol was not related to activation of PPARalpha, but rather was caused by a 9-cis retinoic acid mediated mechanism that involved down-regulation of retinoid X receptor beta. Diets rich in plant products are associated with a lower risk of cardiovascular disease. Our findings suggest that farnesol may contribute to this protective effect by lowering serum TG levels.
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- 2008
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14. Colon carcinogenesis in liver-specific IGF-I-deficient (LID) mice
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Michael C. Archer, Kafi N. Ealey, Wanli Xuan, and Suying Lu
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Cancer Research ,medicine.medical_specialty ,business.industry ,Azoxymethane ,Colorectal cancer ,Growth factor ,medicine.medical_treatment ,Insulin ,Cancer ,medicine.disease_cause ,medicine.disease ,digestive system diseases ,chemistry.chemical_compound ,Endocrinology ,Oncology ,chemistry ,Internal medicine ,medicine ,business ,Carcinogenesis ,Carcinogen ,Aberrant crypt foci - Abstract
Circulating insulin-like growth factor I (IGF-I) is associated with increased risk of colorectal cancer. It is not clear, however, whether IGF-1 plays a direct causative role in colon carcinogenesis or whether it mediates the known promoting effects of insulin. The objective of this study was to determine the role of IGF-1 in colon carcinogenesis using liver-specific IGF-I deficient (LID) mice that exhibit 70% reductions in circulating IGF-I. Female and male LID mice were treated with the colon-specific carcinogen azoxymethane to induce aberrant crypt foci (ACF) or colon tumors. Female LID mice developed significantly fewer ACF and had normal insulin levels compared to controls. Male LID mice, however, were hyperinsulinemic and exhibited no significant differences in ACF development compared to controls. In the tumor study, both male and female LID mice were hyperinsulinemic and had no significant differences in tumor incidence or multiplicity compared to their respective controls. There was a significant 25% reduction in tumor size, however, in both male and female LID mice compared to controls. These data suggest that IGF-I deficiency attenuates the promoting effect of insulin on colon carcinogenesis and that IGF-I is an independent promoter of the growth of established tumors. Our findings implicate both IGF-I and insulin as important promoters of colon cancer development.
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- 2007
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15. Bone abnormalities in adolescent leptin-deficient mice
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Wendy E. Ward, Kafi N. Ealey, Debbie Fonseca, and Michael C. Archer
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Leptin ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Time Factors ,Genotype ,Bone density ,Physiology ,Clinical Biochemistry ,Long bone ,Mice, Obese ,Lumbar vertebrae ,Biochemistry ,Bone and Bones ,Bone remodeling ,Mice ,Cellular and Molecular Neuroscience ,Endocrinology ,Bone Density ,Internal medicine ,medicine ,Animals ,Femur ,Bone mineral ,Lumbar Vertebrae ,Leptin Deficiency ,Dose-Response Relationship, Drug ,business.industry ,Body Weight ,musculoskeletal system ,Biomechanical Phenomena ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Cortical bone ,Bone Diseases ,business - Abstract
Ob/ob and db/db mice have different aberrations in leptin signaling that both lead to abnormalities in bone mineral density (BMD), and bone histological and histomorphometric outcomes. A few studies have directly compared bone metabolism in ob/ob and db/db mice, and biomechanical strength properties that are surrogate measures of fracture risk, have not been extensively studied. This study compared bone mineral content (BMC), BMD and biomechanical strength properties of femurs and lumbar vertebrae among 10 week old male ob/ob, db/db and C57Bl/6 wildtype (WT) mice. Femurs and lumbar vertebrae were specifically studied to determine if trabecular and cortical bone are regulated by leptin in a similar manner in ob/ob and db/db mice. Femurs of ob/ob and db/db mice had lower BMC, BMD and biomechanical strength properties, including peak load, compared to WT mice. In contrast, lumbar vertebrae BMC and BMD did not differ among genotypes, nor did the peak load from compression testing of an individual lumbar vertebra differ among groups. These findings suggest that leptin deficiency in adolescent male mice first results in changes in femurs, a representative long bone, and alterations in lumbar vertebrae may occur later in life.
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- 2006
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16. Effects of dietary folate on the development and progression of mammary tumors in rats †
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Rochelle Martin, Joanne Kotsopoulos, Alan Medline, Richard Renlund, Kyoung-Jin Sohn, Michael C. Archer, Young-In Kim, Stephen W. Hwang, and Suying Lu
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Cancer Research ,medicine.medical_specialty ,Mammary gland ,Weanling ,Adenocarcinoma ,Folic Acid Deficiency ,Biology ,medicine.disease_cause ,Rats, Sprague-Dawley ,Basal (phylogenetics) ,Folic Acid ,Breast cancer ,Oral administration ,Dietary folate ,Internal medicine ,medicine ,Animals ,Anticarcinogenic Agents ,Mammary Neoplasms, Experimental ,Methylnitrosourea ,General Medicine ,medicine.disease ,Diet ,Rats ,medicine.anatomical_structure ,Endocrinology ,Tumor progression ,Female ,Carcinogenesis - Abstract
Epidemiologic studies have suggested that dietary intake and blood levels of folate may be inversely related to the risk of breast cancer. However, epidemiologic evidence has not been consistent nor has it provided unequivocal support for this purported inverse relationship. Recent evidence has also raised a concern that folate supplementation may promote carcinogenesis if provided after neoplastic foci are established in the target organ. This study investigated the effect of dietary folate deficiency and supplementation on the development and progression of mammary tumors in the N-methyl-N-nitrosourea (MNU) rat model. Weanling, female Sprague-Dawley rats were fed diets containing 0, 2 (control) or 8 mg folic acid/kg diet during the initiation or the promotion phase of MNU-induced mammary tumorigenesis. At necropsy, all macroscopic mammary tumors were identified and histologically confirmed. Dietary folate deficiency and supplementation provided during the initiation phase did not significantly modulate the development of mammary tumors. In contrast, dietary folate deficiency provided during the promotion phase significantly inhibited the rate of appearance, incidence, mean volume and weight of adenocarcinomas compared with the control and supplemental diets. Folate supplementation provided during the promotion phase did not significantly modulate mammary tumorigenesis compared with the control group. These data indicate that moderate folate deficiency inhibits, whereas dietary folate supplementation at four times the basal dietary requirement does not promote, the progression of MNU-induced mammary neoplastic foci in this rat model. However, the limitations associated with the route and dose of MNU administration preclude a definitive conclusion concerning the effect of folate status on the initiation of MNU-induced mammary tumorigenesis.
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- 2005
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17. Dietary factors and the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase: Implications for breast cancer development
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Ahmed El-Sohemy, Robin E. Duncan, and Michael C. Archer
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Coenzyme A ,Mevalonic Acid ,Genistein ,Breast Neoplasms ,Reductase ,chemistry.chemical_compound ,Fatty Acids, Omega-3 ,Animals ,Homeostasis ,Humans ,DNA synthesis ,biology ,Terpenes ,Cell growth ,Cholesterol ,Plants ,Diet ,chemistry ,Biochemistry ,HMG-CoA reductase ,Cancer cell ,biology.protein ,Cancer research ,Hydroxymethylglutaryl CoA Reductases ,Cell Division ,Food Science ,Biotechnology - Abstract
A role for mevalonate in cancer development has long been suggested by findings that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity is elevated in malignant cells. Increased synthesis of mevalonate and mevalonate-derived nonsterol isoprenoids supports increased cell proliferation through the activation of growth-regulatory proteins and oncoproteins, and by promoting DNA synthesis. We have recently shown that mevalonate promotes the growth of human breast cancer cells both in culture and as tumors grown in nude mice. Inhibiting mevalonate synthesis, therefore, may be an effective strategy to impair the growth of malignant breast cells. Several dietary compounds with known anti-cancer effects are also reported to inhibit HMG-CoA reductase activity. Here, we review evidence suggesting that inhibition of mevalonate synthesis may mediate the protective effects of cholesterol, plant isoprenoids, genistein, and long-chain n-3 polyunsaturated fatty acids (PUFAs) on experimental breast cancer.
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- 2005
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18. The case for strategic international alliances to harness nutritional genomics for public and personal health
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Jean-Philippe Jais, Lin He, Matthew A. Roberts, Michael C. Archer, Mitchell M. Kanter, Gertrud U. Schuster, Taesun Park, Kaisa Poutanen, Bruce German, Jose M. Ordovas, Warren C. McNabb, Susan J. Fairweather-Tait, Ivana Beatrice Manica da Cruz, Paul Trayhurn, Craig A. Cooney, Su-Ju Lin, Rosane Caetano, Denis R. Lauren, Willard J. Visek, Michael Mayne, Craig H Warden, Ricardo Uauy, Dolores Corella, Wim H. M. Saris, Bruce R. Korf, Ruth Chadwick, Jim Kaput, Norma Ana Pensel, Frans van der Ouderaa, John K. Wiencke, Ruan M. Elliott, Ben van Ommen, Jan-Åke Gustafsson, Yangsoo Jang, Michael J. Gibney, Troy Duster, Sven O. E. Ebbesson, Ruth Birk, Francisco Pérez-Jiménez, Michael Fenech, David Castle, David W. Krempin, Ronald M. Krauss, Kenneth S. Kornman, Jae-Kwan Hwang, Kenneth H. Brown, Rosalynn Gill-Garrison, Lynnette R. Ferguson, Claudine Junien, Kent J. Bradford, Gillies Peter John, John C. Mathers, Xi Zhao-Wilson, Michael Müller, John L. Hartman, Yuri Nikolsky, Jong Ho Lee, Berthold Koletzko, Sue Southon, Karine Clément, Andrew N. Shelling, Peter J. van Bladeren, Jim Felton, John W. Finley, Stephen L. Clarke, Bruce N. Ames, Hans Joost, Gilbert A. Leveille, Stephen Barnes, Jean-Daniel Zucker, Bradford Towne, Warren A. Kibbe, Nancy Fogg-Johnson, Peter Morgan, Raymond L. Rodriguez, E. Shyong Tai, Amelia Bartholomew, Kevin Dawson, Wasyl Malyj, Jack Winkler, Dominique Langin, John A. Milner, Rick Weiss, Lindsay H. Allen, Hannelore Daniel, George L. Wolff, Artemis P. Simopoulos, and TNO Kwaliteit van Leven
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Knowledge management ,Nutritional genomics ,Biomedical Research ,genetic association ,030309 nutrition & dietetics ,genotype ,International Cooperation ,Medicine (miscellaneous) ,Variation (Genetics) ,Human genetic variation ,medical research ,gene–nutrient interactions ,Voeding, Metabolisme en Genomica ,Eating ,Nutrigenomics ,environmental factor ,genetic variability ,Global health ,Nutritional Physiological Phenomena ,Health diaparities ,immune function ,2. Zero hunger ,0303 health sciences ,Nutrition and Dietetics ,strategic international alliances ,article ,Genomics ,diabetes-related traits ,dietary fiber ,Health equity ,Metabolism and Genomics ,3. Good health ,messenger-rna ,Health ,Metabolisme en Genomica ,Nutrition, Metabolism and Genomics ,health diaparities ,medicine.medical_specialty ,Research program ,hapmap project ,population stratification ,heredity ,phenotype ,Biology ,Environment ,Strategic international alliances ,nutritional health ,03 medical and health sciences ,Gene interaction ,nutrigenomics ,SDG 3 - Good Health and Well-being ,Voeding ,medicine ,Animals ,Humans ,complex diseases ,human ,030304 developmental biology ,gene identification ,VLAG ,Nutrition ,nonhuman ,business.industry ,Genome, Human ,Public health ,Research ,Genetic Variation ,population genetics ,Gene-nutrient interactions ,cultural factor ,Nutrition Physiology ,Biotechnology ,Disease Models, Animal ,Harness ,molecular genetics ,business ,dietary intake ,public health service ,coronary-heart-disease ,carbohydrate ingestion - Abstract
Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries. © The Authors 2005.
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- 2005
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19. Geraniol and β-ionone inhibit proliferation, cell cycle progression, and cyclin-dependent kinase 2 activity in MCF-7 breast cancer cells independent of effects on HMG-CoA reductase activity
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Michael C. Archer, Ahmed El-Sohemy, Dominic Lau, and Robin E. Duncan
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Time Factors ,Acyclic Monoterpenes ,Gene Expression ,Breast Neoplasms ,Reductase ,Biochemistry ,S Phase ,Cyclin-dependent kinase ,CDC2-CDC28 Kinases ,Tumor Cells, Cultured ,Humans ,Cell Proliferation ,Pharmacology ,Dose-Response Relationship, Drug ,biology ,Terpenes ,Cell growth ,Cell Cycle ,Cyclin-Dependent Kinase 2 ,Cyclin-dependent kinase 2 ,G1 Phase ,Cell cycle ,Hydroxymethylglutaryl-CoA reductase ,Cell biology ,HMG-CoA reductase ,Cancer cell ,biology.protein ,Hydroxymethylglutaryl CoA Reductases ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Norisoprenoids ,Cell Division - Abstract
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the formation of mevalonate, a precursor of cholesterol that is also required for cell proliferation. Mevalonate depletion results in a G1 phase cell cycle arrest that is mediated in part by impaired activity of cyclin-dependent kinase (CDK) 2, and decreased expression of positive regulators of G1 to S phase progression. Inhibition of mevalonate synthesis may, therefore, be a useful strategy to impair the growth of malignant cells. Plant isoprenoids, including beta-ionone and geraniol, have previously been shown to inhibit rodent mammary tumor development, and rodent and avian hepatic HMG-CoA reductase activity. We hypothesized that the putative anti-proliferative and cell cycle inhibitory effects of beta-ionone and geraniol on MCF-7 human breast cancer cells in culture are mediated by mevalonate depletion resulting from inhibition of HMG-CoA reductase activity. Flow cytometric analysis showed a G1 arrest in isoprenoid-treated MCF-7 cells, and also a G2/M arrest at higher concentrations of isoprenoids. These compounds minimally affected the growth of MCF-10F normal breast epithelial cells. Both beta-ionone and geraniol inhibited CDK 2 activity and dose-dependently decreased the expression of cyclins D1, E, and A, and CDK 2 and 4, without changing the expression of p21cip1 or p27kip1. Although both beta-ionone and geraniol also inhibited MCF-7 proliferation, only geraniol inhibited HMG-CoA reductase activity. While these effects were significantly correlated (r2=0.89, P
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- 2004
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20. Cyclooxygenase-2 inhibitor celecoxib inhibits promotion of mammary tumorigenesis in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids
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Alaa Badawi, Michael C. Archer, Ahmed El-Sohemy, Suying Lu, and Xizhong Zhang
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Cancer Research ,medicine.medical_specialty ,food.ingredient ,Adipose tissue ,Soybean oil ,Rats, Sprague-Dawley ,food ,Dietary Fats, Unsaturated ,Fatty Acids, Omega-6 ,Internal medicine ,Mammary tumorigenesis ,medicine ,Animals ,Anticarcinogenic Agents ,Cyclooxygenase Inhibitors ,chemistry.chemical_classification ,Sulfonamides ,Cyclooxygenase 2 Inhibitors ,Dose-Response Relationship, Drug ,biology ,Mammary Neoplasms, Experimental ,Methylnitrosourea ,Lipid metabolism ,Dietary Fats ,Rats ,Isoenzymes ,Endocrinology ,Oncology ,chemistry ,Celecoxib ,Cyclooxygenase 2 ,Prostaglandin-Endoperoxide Synthases ,Toxicity ,Fatty Acids, Unsaturated ,biology.protein ,Pyrazoles ,Female ,Cyclooxygenase ,medicine.drug ,Polyunsaturated fatty acid - Abstract
The objective of this investigation was to determine whether celecoxib, a highly specific inhibitor of cyclooxygenase-2 (COX-2), inhibits the promotion phase of mammary tumorigenesis in rats fed a high fat diet rich in n-6 polyunsaturated fatty acids (PUFAs) that is known to induce COX-2 expression. Sixty female Sprague-Dawley rats were initially maintained on an AIN-93G diet. At 50 days of age they received a single i.p. injection of methylnitrosourea (MNU). One week later, all rats were switched to a modified AIN-93G diet containing 18% safflower oil plus 3% soybean oil. Half of the rats also began receiving 1500 ppm celecoxib in the diet and the control and experimental diets were continued for a further 23 weeks. Celecoxib significantly decreased both the final tumor incidence (63.3% in the celecoxib group versus 82.2% in the control group, P0.05) and tumor multiplicity (0.9+/-0.2 tumors/rat in the celecoxib group versus 2.3+/-0.3 tumors/rat in the control group, P0.05). At the termination of the experiment, body weights were significantly lower in the celecoxib group compared to controls (330.6+/-6.1 versus 401.5+/-10.9 g respectively, P0.05) although there was no evidence of toxicity and food intakes were not different for the two groups. Fasting serum triglycerides and abdominal adipose tissue accumulation were lower in the celecoxib group compared to controls (49.3+/-4.4 versus 82.8+/-12.6 mg/dL, P0.05, and 7.2+/-0.3 versus 11.3+/-0.4% of body weight, P0.01, respectively). These results show that administration of celecoxib to rats in a high fat diet rich in n-6 PUFAs suppresses the promotion of mammary tumorigenesis induced by MNU. This inhibition may be due to the effects of celecoxib on lipid metabolism as well as COX-2.
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- 2002
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21. Effects of dietary conjugated linoleic acid on the expression of uncoupling proteins in mice and rats
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Michael C. Archer, Ahmed El-Sohemy, and Kafi N. Ealey
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Male ,medicine.medical_specialty ,Clinical chemistry ,Conjugated linoleic acid ,Blotting, Western ,Adipose tissue ,White adipose tissue ,Biology ,Biochemistry ,Ion Channels ,Mitochondrial Proteins ,Rats, Sprague-Dawley ,Mice ,chemistry.chemical_compound ,Mammary Glands, Animal ,Adipose Tissue, Brown ,Internal medicine ,Brown adipose tissue ,medicine ,Animals ,Linoleic Acids, Conjugated ,Uncoupling Protein 2 ,RNA, Messenger ,UCP3 ,integumentary system ,Muscles ,Organic Chemistry ,Membrane Transport Proteins ,Proteins ,food and beverages ,Skeletal muscle ,Organ Size ,Cell Biology ,Blotting, Northern ,Dietary Fats ,Rats ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,Liver ,chemistry ,Female ,lipids (amino acids, peptides, and proteins) ,Carrier Proteins ,Lipidology - Abstract
CLA inhibits mammary cancer and reduces body fat accumulation in rodents. It is not known whether uncoupling proteins (UCP), which are modulators of energy balance and metabolism, play a role in these actions of CLA. To determine the effects of dietary CLA on the expression of UCP in various tissues, 5-wk-old Sprague-Dawley rats and C57Bl/6 mice were fed diets containing 1% CLA for 3 wk. CLA treatment reduced adipose depot weights in both rats and mice but had no significant effects on body weight. There was a species-specific effect of CLA on the expression of UCP. Whereas CLA did not affect the expression of UCP in most tissues in rats, mice fed CLA had increased expression of UCP2 in the mammary gland, brown adipose tissue (BAT), and white adipose tissue (WAT). Furthermore, UCP1 and UCP3 mRNA and protein levels in BAT were significantly lower in CLA-fed mice compared to controls. Skeletal muscle UCP3 mRNA was unchanged, but UCP3 protein levels were significantly increased in mice, suggesting translational or posttranslational regulation of this protein. Results from this study suggest that alterations in the expression of UCP in mice may be related to the previously reported effects of dietary CLA in lowering adiposity and increasing FA oxidation. In rats, however, induction of UCP is not likely to be responsible for fat reduction or for the inhibitory action of CLA on mammary carcinogenesis.
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- 2002
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22. Tissue-specific resistance to cancer development in the rat: phenotypes of tumor-modifier genes
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Geoffrey A. Wood, Michael C. Archer, and James E. Korkola
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Cancer Research ,Pathology ,medicine.medical_specialty ,Genotype ,Cellular differentiation ,Mammary gland ,Mammary Neoplasms, Animal ,Biology ,medicine.disease_cause ,Immune system ,Peripheral Nervous System Neoplasms ,Neoplasms ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Liver Neoplasms ,Cancer ,Oncogenes ,General Medicine ,medicine.disease ,Phenotype ,Rats ,Immunosurveillance ,medicine.anatomical_structure ,Organ Specificity ,Apoptosis ,Cancer research ,Carcinogenesis - Abstract
Resistance to carcinogenesis in the rat is both strain- and tissue-specific. The phenotypic characteristics of resistance in the mammary gland, liver and peripheral nervous system (PNS) are strikingly similar. In all three tissues, initiation is intact with subsequent formation of preneoplastic cells and lesions. In the mammary gland and PNS, activation of the Ha-ras and neu proto-oncogenes, respectively, takes place. A number of different modifier genes are involved in resistance, many of which appear to be tissue-specific in their action with no overlap between strains. A single resistance phenotype, however, involving the formation, growth and subsequent loss of preneoplastic lesions is common to all three tissues of resistant strains. In the PNS, there is evidence that preneoplastic cells are eliminated by apoptosis or immunosurveillance. In the mammary gland and liver, the immune system is not involved in the loss of preneoplastic lesions and there are no clear differences between susceptible and resistant strains in the kinetics of proliferation and apoptosis of preneoplastic cells. The evidence to date favors a mechanism in which preneoplastic cells from these tissues undergo a process of remodeling/redifferentiation to yield cells with a normal phenotype. Identification of human homologues of rodent tumor-modifier genes will result in a better understanding of cancer development and potentially provide new strategies for prevention and therapy.
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- 2002
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23. Matrix Metalloproteinases-2 and 9 Do Not Play a Role in the Growth of Preneoplastic Liver Lesions in F344 Rats
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Michael C. Archer and Geoffrey A. Wood
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0301 basic medicine ,Alkylating Agents ,medicine.medical_specialty ,Pathology ,Time Factors ,Matrix metalloproteinase ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Gelatinase ,Diethylnitrosamine ,Glutathione Transferase ,chemistry.chemical_classification ,Chemistry ,Liver Neoplasms ,Glutathione ,medicine.disease ,Rats, Inbred F344 ,Liver regeneration ,Rats ,030104 developmental biology ,Endocrinology ,Enzyme ,medicine.anatomical_structure ,Liver ,Matrix Metalloproteinase 9 ,030220 oncology & carcinogenesis ,Hepatocyte ,Matrix Metalloproteinase 2 ,Precancerous Conditions ,Batimastat ,Densitometry - Abstract
Matrix metalloproteinases- (MMPs) 2 and 9 (gelatinases A and B) have been implicated in tumor invasion and metastasis, and recent studies have shown increased levels of these enzymes during recovery from partial hepatectomy (PH) in rats. F344 rats are highly susceptible to the growth of glutathione S-transferase 7-7- (GST 7-7) positive preneoplastic liver lesions promoted using the modified resistant hepatocyte (RH) protocol. Since the RH protocol consists of 2-acetylaminofluorene (2-AAF) followed by a PH, we reasoned that MMP-2 and -9 might be critical for the growth of lesions. Using gelatin zymography, we examined the expression of these enzymes in the livers of F344 rats treated with the RH protocol and sacrificed on Days 2, 4, 7, 14, and 21 after 2-AAF/PH. We found increases in both pro- and active MMP-2 and -9 over baseline levels, with the highest levels occurring on Day 7 post-PH. Also, a 54-kDa band, likely to be proMMP-1, was elevated in a pattern similar to MMP-2 and -9. In contrast to F344 rats, identically treated Copenhagen rats that are highly resistant to promotion of liver lesion growth using the RH protocol had significantly lower levels of proMMP-1 and -2. To test the importance of these MMPs to the growth of liver lesions, F344 rats that had been initiated with diethylnitrosamine were treated using the RH protocol. They then received either the MMP inhibitor batimastat (30 mg/kg, intraperitoneally) or vehicle alone daily from Day 3 to 20 post-PH and were sacrificed on Day 21. There were no differences in the percentage of liver volume occupied by GST 7-7-positive lesions (19.1 ± 4.84 vs 19.4 ± 3.31, treated versus vehicle, mean ± SEM) or liver weight as a percentage of body weight (4.11% ± 0.15 vs 4.07% ± 0.18, treated versus vehicle, mean ± SEM) between the treated and control groups. Treatment of rats with batimastat clearly did not affect lesion growth or liver regeneration following the RH protocol. These results suggest that increases in gelatinase expression during the RH protocol are a result of the promotional stimulus rather than a mechanism by which 2-AAF/PH causes lesion growth.
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- 2001
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24. Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat
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Brock G. Chittim, Daniel Desaulniers, Michael G. Wade, Jack Yang, Garth Perkins, Karen Leingartner, Jose Russo, and Michael C. Archer
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Alkylating Agents ,Insecticides ,medicine.medical_specialty ,Polychlorinated Dibenzodioxins ,Dichlorodiphenyl Dichloroethylene ,Health, Toxicology and Mutagenesis ,medicine.medical_treatment ,Metabolite ,Intraperitoneal injection ,Mammary gland ,Body weight ,Carcinogenic process ,DDT ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Breast cancer ,Pregnancy ,Internal medicine ,medicine ,Animals ,Breast ,Mammary tumor ,Dose-Response Relationship, Drug ,Public Health, Environmental and Occupational Health ,Mammary Neoplasms, Experimental ,Methylnitrosourea ,medicine.disease ,Polychlorinated Biphenyls ,Rats ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Prenatal Exposure Delayed Effects ,Environmental Pollutants ,Female ,Research Article - Abstract
The role of organochlorine (OC) exposure in the etiology of breast cancer remains controversial. Thus, our objective was to determine whether the most abundant and toxic OCs found in human milk could, when ingested during the neonatal period, modulate the development of mammary tumors in the rat. We prepared a mixture composed of p,p'-dichlorodiphenyltrichloroethane (DDT), its major metabolite, p,p'-dichlorodiphenyldichloroethene (DDE), and 19 polychlorinated biphenyls (PCB) based on their concentrations found in the milk of Canadian women. Neonate rats at 1, 5, 10, 15, and 20 days of age were gavaged with this mixture, at 10, 100, and 1,000 times the amount that a human baby would consume. An additional group received 2.5 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg body weight (bw) by gavage at 18 days of age, instead of the mixture. On day 21, all treatment groups, except for a control group and a 1,000-mix group, received a single intraperitoneal injection of methylnitrosourea (MNU, 30 mg/kg bw), the initiator of the carcinogenic process. The average number of rats per treatment group was 33. Rats were sacrificed when their tumors reached 1 cm in size, or at 308 days of age. We prepared mammary tumors and mammary gland whole mounts for histologic analysis. There were no significant effects when only the malignant or only the benign tumors were considered. After all benign and malignant lesions were pooled, the number of mammary tumors differed among all MNU-treated groups (p = 0.02) with more lesions developing in the MNU-1,000[times] (median = 4.5; p = 0.05) and MNU-TCDD (median = 5.5; p = 0.07) compared to the MNU-0 rats (median = 2). Compared to the MNU-0 group, the percentage of rats that developed palpable tumors (benign plus malignant) was slightly higher (p = 0.06) in the MNU-TCDD group, but not in the MNU-1,000[times] group. The percentage of palpable tumors that were malignant was higher (p = 0.02) in the MNU-100[times] group (15/16, 94%) than in the MNU-0 group (10/18, 56%). The highest dose of the mixture delayed (p = 0.03) the development of tumors, but this was not observed with the MNU-TCDD treatment. These results suggest that neonatal exposure to high doses of organochlorines could favor the development of MNU-induced mammary lesions, but also delays the development of palpable tumors in the rat.
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- 2001
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25. Induction of Hepatic Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) in Rats by Dietary n-6 Polyunsaturated Fatty Acids
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Michael C. Archer, Amit Ghoshal, Zhaoming Xu, and Geoffrey A. Wood
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medicine.medical_specialty ,medicine.medical_treatment ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Insulin-like growth factor-binding protein ,Rats, Sprague-Dawley ,Insulin-like growth factor ,Liver Neoplasms, Experimental ,Insulin resistance ,Dietary Fats, Unsaturated ,Downregulation and upregulation ,Insulin-Like Growth Factor II ,Fatty Acids, Omega-6 ,Internal medicine ,medicine ,Animals ,Humans ,Insulin ,RNA, Messenger ,Insulin-Like Growth Factor I ,Receptor ,chemistry.chemical_classification ,Growth factor ,medicine.disease ,Rats ,Insulin-Like Growth Factor Binding Protein 1 ,Endocrinology ,Insulin-Like Growth Factor Binding Protein 4 ,Liver ,chemistry ,Fatty Acids, Unsaturated ,Hepatocytes ,biology.protein ,Female ,Insulin Resistance ,Cell Division ,Corn oil ,Polyunsaturated fatty acid - Abstract
The insulin-like growth factors (IGFs) are mitogenic polypeptides that have been linked to a variety of normal physiological processes as well as neoplasia. Overexpression of several components of the IGF system is associated with hepatocarcinogenesis in humans and rodents. In rat liver, diets rich in n-6 polyunsaturated fatty acid (PUFA) enhance the development of preneoplastic lesions and tumors. Therefore, the objective of this study was to determine the effect of these dietary fatty acids on the hepatic expression of the various components of the IGF system. The mRNA levels of IGF-1 and the type 1 receptor were not different in livers of rats fed a diet containing 20% corn oil (CO) compared with those fed 5% CO. Analysis of the IGF binding proteins revealed that insulin-like growth factor binding protein-1 (IGFBP-1) levels were altered by the amount and type of dietary fat. A 2.5-fold induction of IGFBP-1 mRNA occurred within 1 week after the animals were fed the 20% corn oil diet compared with those fed 5% CO and was further enhanced to over 6-fold after 1 month. Furthermore, IGFBP-1 protein was only detectable in the livers of animals fed the 20% CO diet. Induction of IGFBP-1 mRNA (4.5-fold) also occurred in rats fed a high-fat diet containing safflower (rich in n-6 PUFAs) compared with those fed a high-fat diet containing menhaden oil (rich in n-3 PUFAs). The induction of IGFBP-1 mRNA was independent of serum insulin levels and the development of insulin resistance. Since IGFBP-1 mRNA is upregulated in regenerating liver, we reasoned that the induction of IGFBP-1 mRNA may be associated with an increase in cell proliferation; however, no difference was observed in the hepatic labeling index of rats fed the 20% CO compared with the 5% CO diet. In summary, these studies show a striking induction by dietary n-6 PUFAs of hepatic IGFBP-1, a protein that has been implicated in liver cancer development.
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- 2000
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26. Regulation of mevalonate synthesis in low density lipoprotein receptor knockout mice fed n-3 or n-6 polyunsaturated fatty acids
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Ahmed El-Sohemy and Michael C. Archer
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medicine.medical_specialty ,Clinical chemistry ,Mevalonic Acid ,Blood lipids ,Reductase ,Biochemistry ,Mice ,chemistry.chemical_compound ,High-density lipoprotein ,Internal medicine ,medicine ,Animals ,Mice, Knockout ,chemistry.chemical_classification ,biology ,Cholesterol ,Organic Chemistry ,Cell Biology ,Diet ,Endocrinology ,Liver ,Receptors, LDL ,chemistry ,HMG-CoA reductase ,LDL receptor ,Fatty Acids, Unsaturated ,biology.protein ,Female ,Hydroxymethylglutaryl CoA Reductases ,lipids (amino acids, peptides, and proteins) ,Polyunsaturated fatty acid - Abstract
3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, catalyzes the formation of mevalonate which is also required for cell proliferation. Changes in HMG-CoA reductase may mediate the differential effects of n-3 and n-6 polyunsaturated fatty acids (PUFA) on experimental mammary tumorigenesis, but the mechanisms by which these fatty acids regulate HMG-CoA reductase are unclear. To determine whether the low density lipoprotein receptor (LDL-R) is required for this regulation, groups of female LDL-R knockout (-/-) and wild-type (+/+) mice were fed 7% fat diets rich in either n-3 (menhaden oil) or n-6 (safflower oil) PUFA for 1 wk. Dietary PUFA and deletion of the LDL-R had independent effects on HMG-CoA reductase and serum lipids, and a significant diet-gene interaction was observed. The effects of PUFA on HMG-CoA reductase in the mammary gland, but not the liver, were mediated by the LDL-R. We also observed that differences in HMG-CoA reductase and serum LDL-cholesterol, high density lipoprotein cholesterol, and triglycerides between -/- and +/+ mice were dependent on whether the mice were fed n-3 or n-6 PUFA. Differences between -/- and +/+ mice were much greater when animals were fed n-6 PUFA rather than n-3 PUFA. These results show that the LDL-R mediates the effects of PUFA on HMG-CoA reductase in the mammary gland but not the liver. Furthermore, the composition of dietary PUFA profoundly influences the effects of deleting the LDL-R on HMG-CoA reductase and serum lipids and suggests that diet may influence the phenotype of other knock-out or transgenic animals.
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- 1999
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27. Resistance to the promotion of glutathione S-transferase 7-7-positive liver lesions in Copenhagen rats
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Geoffrey A. Wood, Dittakavi S. R. Sarma, and Michael C. Archer
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Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Time Factors ,Apoptosis ,Tumor initiation ,Biology ,Lesion ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Species Specificity ,Internal medicine ,medicine ,Animals ,Hepatectomy ,Diethylnitrosamine ,Glutathione Transferase ,Rats, Inbred Strains ,General Medicine ,Glutathione ,2-Acetylaminofluorene ,Rats, Inbred F344 ,Rats ,medicine.anatomical_structure ,Endocrinology ,Glutathione S-transferase ,Bromodeoxyuridine ,chemistry ,Hepatocyte ,biology.protein ,Tumor promotion ,medicine.symptom ,Precancerous Conditions ,Cell Division - Abstract
Previously, we have shown that Copenhagen (Cop) rats are highly resistant to the induction of putative preneoplastic, glutathione S-transferase 7-7 (GST 7-7)-positive liver lesions following treatment with a modified resistant hepatocyte protocol. The objective of the current study was to establish the time course for the development of resistance and examine potential resistance mechanisms in Cop rats using F344 rats as susceptible controls. Male Cop and F344 rats (n = 25), 7-8 weeks of age, were initiated with diethylnitrosamine (200 mg/kg) and promoted 3 weeks later with four doses of 2-acetylaminofluorene (20 mg/kg) and a 2/3 partial hepatectomy (PH). Groups of rats from each strain were killed on days 2, 4, 7, 14 and 21 post-PH, 2 h after receiving bromodeoxyuridine. Cop livers contained similar numbers of GST 7-7-positive lesions to F344 livers on days 2 and 4 post-PH. The percent volume of liver occupied by these lesions did not differ between the strains on days 2, 4 and 7 post-PH. On day 14, however, approximately 29% of the liver volume in F344 rats was occupied by lesions, whereas in Cop rats this was significantly less (approximately 9%, P0.001). On day 21, lesions occupied approximately 58% of F344 rat livers and only approximately 6% of Cop livers. Despite these differences, the labeling index of hepatocytes was not significantly different between the strains at any time point, either within lesions or within surrounding normal liver. Furthermore, the apoptotic indices were not different between the strains at any time. However, differences were found in the extent of lesion remodeling (redifferentiation) and in the pattern of oval cell response following PH in Cop livers. By day 14 post-PH, approximately 76% of Cop liver lesions showed evidence of remodeling, compared with only approximately 14% of F344 lesions. The oval cell response to PH was equivalent in the two strains up to day 4 post-PH but by day 7, in F344 livers there was extensive migration of these cells into the liver parenchyma, whereas in Cop livers, the response remained localized to the portal regions. These results suggest that Cop resistance occurs at the promotion stage and not the initiation stage of carcinogenesis. Resistance appears not to be due to a lower proliferation rate nor to a higher apoptotic rate within Cop lesions. Precocious remodeling and/or a diminished oval cell response, however, may contribute to the resistance of Cop rats to the growth of GST 7-7-positive hepatic lesions.
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- 1999
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28. Effect of hormonal status on the expression of the cyclooxygenase 1 and 2 genes and prostaglandin synthesis in rat mammary glands
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Michael C. Archer and Alaa Badawi
- Subjects
medicine.medical_specialty ,Physiology ,Ovariectomy ,Mammary gland ,Gene Expression ,Prostaglandin ,Biochemistry ,Dinoprostone ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mammary Glands, Animal ,Pregnancy ,Internal medicine ,Lactation ,medicine ,Animals ,Involution (medicine) ,RNA, Messenger ,Northern blot ,Pharmacology ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Membrane Proteins ,Epithelial Cells ,Cell Biology ,Blotting, Northern ,Hormones ,Rats ,Isoenzymes ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Cyclooxygenase 2 ,Prostaglandin-Endoperoxide Synthases ,Cyclooxygenase 1 ,biology.protein ,Ovariectomized rat ,Female ,Cyclooxygenase ,Stromal Cells ,Hormone - Abstract
Hormonal effects on mammary carcinogenesis have been linked to prostaglandin (PG) synthesis. The purpose of the present study was to examine the expression of the cyclooxygenase (COX) 1 and 2 genes and levels of PG synthesis in the mammary glands of rats that have different levels of susceptibility to mammary gland carcinogenesis associated with pregnancy, lactation, post-lactation involution, and ovariectomy. The expression of COX-1 mRNA, measured by Northern blot analysis, was similar in virgin, lactating, pregnant, and post-lactational animals of the same age. Ovariectomized animals exhibited significantly lower levels of COX-1 mRNA (approximately 40%) compared to the sham-operated controls or the ovariectomized animals treated with estradiol and progesterone. COX-2 mRNA, measured by RT-PCR, was detectable only in the mammary glands of lactating animals and ovariectomized animals administered estradiol and progesterone. Induction on COX-2 expression occurred in both stromal and epithelial cells in lactating rat mammary glands. COX enzymatic activities, determined by measuring the conversion rate of [1-14 C]-arachadonic acid to prostanoids, showed that lactating animals had a significantly higher activity compared to virgin (approximately 40%), pregnant (approximately 30%), or postlactational animals (approximately 40%). Ovariectomized animals had significantly lower COX enzymatic activity compared to the sham operated animals. Significant induction of COX activity, however, was observed in ovariectomized animals administered estradiol and progesterone. These changes in COX enzymatic activity were paralleled by similar changes in the mammary gland PGE2 content, measured by enzyme immunoassay. Our results suggest that the effect of hormones on the genesis of mammary cancer in the rat may be mediated, at least in part, by their effects on COX-2 expression and PG synthesis.
- Published
- 1998
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29. The effect of dietary n-3 and n-6 polyunsaturated fatty acids on the expression of cyclooxygenase 1 and 2 and levels of p21ras in rat mammary glands
- Author
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Ahmed El-Sohemy, Alaa Badawi, Michael C. Archer, L L Stephen, and A K Ghoshal
- Subjects
Cancer Research ,medicine.medical_specialty ,Oncogene Protein p21(ras) ,Biology ,Dinoprostone ,P21 RAS Protein ,Rats, Sprague-Dawley ,Mammary Glands, Animal ,Internal medicine ,Gene expression ,medicine ,Animals ,RNA, Messenger ,DNA Primers ,chemistry.chemical_classification ,Menhaden Oil ,Base Sequence ,Membrane Proteins ,General Medicine ,Dietary Fats ,Enzyme assay ,Rats ,Proto-Oncogene Proteins p21(ras) ,Isoenzymes ,Genes, ras ,Endocrinology ,chemistry ,Cyclooxygenase 2 ,Prostaglandin-Endoperoxide Synthases ,Toxicity ,Cyclooxygenase 1 ,Fatty Acids, Unsaturated ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,Cyclooxygenase ,Polyunsaturated fatty acid - Abstract
Dietary n-6 polyunsaturated fatty acids (PUFAs) promote rat mammary cancer while n-3 PUFAs are inhibitory. The purpose of this study was to determine whether the fats exert their effects by altering the expression of genes that affect cancer development. Therefore, we have examined the effect of PUFAs on the expression of the cyclooxygenase (COX) 1 and 2 genes that are involved in prostaglandin biosynthesis. We also investigated the effect of dietary PUFAs on the expression of the p21ras protein and Ha-ras mRNA. Rats were fed either low- (7%; LF) or high- (21%; HF) fat diets that were rich in either n-6 PUFAs (safflower oil, S) or n-3 PUFAs (menhaden oil, M) for 3 weeks. COX-1 mRNA levels were approximately the same in groups fed diets containing either level of menhaden oil, but were increased by approximately 30% in the LFS and HFS groups (P0.05). Transcripts of the inducible COX-2 gene were not detectable in the menhaden oil groups, but this gene was expressed in animals fed either level of safflower oil and in the HFS group was associated with increased levels of COX enzymatic activity and production of PGE2. Animals fed safflower oil had elevated levels of p21ras protein compared to animals fed menhaden oil. Ha-ras mRNA was increased by approximately 35% in animals fed HFS compared to the group fed HFM (P0.05). These results demonstrate that dietary n-6 PUFAs upregulate COX-2 and, to some extent, COX-1 expression. There was a concomitant increase in COX enzyme activity and PG synthesis in the mammary glands of rats fed high levels of n-6 PUFAs. Together with associated changes in p21ras expression, these results may explain, at least in part, the promoting effects of dietary n-6 PUFAs on mammary carcinogenesis.
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- 1998
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30. Rapid quantitation of thermal oxidation products in fats and oils by1H‐NMR spectroscopy
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Michael C. Archer, A. A. Grey, Chi Ming Yang, and W. R. Bruce
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Cancer Research ,Hot Temperature ,Magnetic Resonance Spectroscopy ,Nutrition and Dietetics ,Triglyceride ,Medicine (miscellaneous) ,Hydrogen Peroxide ,Nuclear magnetic resonance spectroscopy ,Fats ,chemistry.chemical_compound ,Oncology ,chemistry ,Tallow ,Fatty Acids, Unsaturated ,Proton NMR ,Animals ,Organic chemistry ,Cattle ,Corn Oil ,Spectroscopy ,Oxidation-Reduction ,Two-dimensional nuclear magnetic resonance spectroscopy ,Triglycerides ,Unsaturated fatty acid ,Corn oil - Abstract
This work describes the application of high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy to the study of the thermal peroxidation of beef tallow and corn oil under standardized conditions. The approach provides a rapid, quantitative method for determining the degree of oxidation of unsaturated fatty acids in animal and vegetable fats and oils by quantitating the decreasing intensities of 1H-NMR peaks for allylic and olefinic protons in unsaturated fatty acid chains of triglycerides and the increasing peak intensities of hydroperoxide and saturated and alpha, beta-unsaturated aldehydic protons in relation to the less labile protons in the triglyceride molecule. Two-dimensional correlation spectroscopy analysis of highly oxidized beef tallow (180 degrees C for 24 h) suggested that the unsaturated aldehydes that persisted were apparently associated with carboxy groups.
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- 1998
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31. Thermally oxidized dietary fat and colon carcinogenesis in rodents
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Michael C. Archer, D. Stamp, W. R. Bruce, Alan Medline, Cyril W.C. Kendall, and Chi Ming Yang
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Male ,Cancer Research ,Hot Temperature ,Colon ,Medicine (miscellaneous) ,Apoptosis ,digestive system ,Fats ,Mice ,Animals ,Medicine ,Food science ,Peroxide value ,Acrolein ,Colonic disease ,Dietary fat ,Carcinogen ,Animal fat ,Nutrition and Dietetics ,business.industry ,Dietary Fats ,Rats, Inbred F344 ,digestive system diseases ,Peroxides ,Rats ,Colon carcinogenesis ,Beef Tallow ,Oncology ,Biochemistry ,Colonic Neoplasms ,Cattle ,Corn Oil ,business ,Oxidation-Reduction ,Aberrant crypt foci - Abstract
Thermally oxidized animal fat (beef tallow) was assessed for colon cancer-promoting and -initiating activity in F-344 rats and CF-1 mice with the use of the aberrant crypt focus (ACF) assay. In two promotion studies, extensively oxidized beef tallow (110 degrees C for 144-168 h, peroxide value approx 200 meq/kg, with80% loss of allylic and olefinic protons) had relatively little effect on the growth of ACF in F-344 rats. The multiplication constant for treatment/control of ACF size in aberrant crypts per ACF at 100 days was 1.07 (95% confidence interval = 1.01-1.14) and 0.98 (95% confidence interval = 0.91-1.06). ACF size was not affected by less extensively oxidized beef tallow or by a 10-fold reduction of dietary alpha-tocopherol during the growth of the ACF. In initiation studies, extensively oxidized beef tallow administered by gavage increased the number of animals with ACF and the number of ACF per colon (11 of 23 and 5 of 29 animals with ACF; 1.09 +/- 0.29 and 0.21 +/- 0.09 ACF/colon, respectively). Less severely oxidized beef tallow was without effect. Further studies with CF-1 mice confirmed that extensively oxidized beef tallow increased numbers of animals with ACF and average ACF per colon. The unsaturated aldehyde acrolein was without effect in the ACF assay. These data suggest that highly thermolyzed beef tallow contains an uncharacterized initiator or leads to conditions in which spontaneously initiated ACF are increased.
- Published
- 1998
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32. Resistance of Copenhagen rats to chemical induction of glutathione S- transferase 7-7-positive liver foci
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Dittakavi S. R. Sarma, James E. Korkola, Geoffrey A. Wood, Valentia M. Lee, and Michael C. Archer
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Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Necrosis ,Drug Resistance ,CCL4 ,Tumor initiation ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Species Specificity ,Internal medicine ,medicine ,Animals ,Hepatectomy ,Diethylnitrosamine ,Glutathione Transferase ,biology ,Methylnitrosourea ,General Medicine ,Glutathione ,2-Acetylaminofluorene ,Rats, Inbred F344 ,Rats ,medicine.anatomical_structure ,Glutathione S-transferase ,Endocrinology ,Liver ,chemistry ,Enzyme Induction ,Hepatocyte ,Carcinogens ,Carbon tetrachloride ,biology.protein ,medicine.symptom - Abstract
Copenhagen (Cop) rats are completely resistant to the chemical induction of mammary adenocarcinomas, but their susceptibility to hepatocarcinogenesis is virtually unknown. Rat liver is a well-characterized and easily manipulated tissue in which to study carcinogenesis. Therefore, if Cop rats are resistant to hepatocarcinogenesis, studies into resistance mechanisms may be feasible. Male Cop and F344 rats, 7-8 weeks old, were initiated using either N-nitrosodiethylamine (DEN) (200 mg/kg, i.p.) or a two-thirds partial hepatectomy (PH) followed by N-methyl-N-nitrosourea (MNU) (60 mg/kg, i.p.). The rats were then promoted using a modified resistant hepatocyte (RH) protocol (a combination of four doses of 2-acetylaminofluorene (2-AAF) and a single dose of CCl4 that provides a selective mitotic stimulus for initiated cells). Six weeks after initiation the rats were killed and liver sections were stained for glutathione S-transferase 7-7 (GST 7-7), a marker for putative preneoplastic hepatocytes. Cop rats were found to be highly resistant, having a approximately 9- and approximately 27-fold smaller percentage of liver area occupied by GST 7-7-positive foci than susceptible F344 rats following initiation by DEN and MNU respectively. Furthermore, gross liver nodules did not form in any of the Cop rats, whereas all F344 rat livers contained nodules. Hepatic necrosis caused by DEN during initiation, and CCl4 during promotion is necessary to stimulate compensatory hepatocyte division. We demonstrated that these agents do indeed increase serum transaminase levels and produce histologic evidence of necrosis in Cop rats. In order for liver foci to grow rapidly in the RH protocol, the surrounding normal hepatocytes must be mito-inhibited by 2-AAF. We found that the degree of mito-inhibition of normal hepatocytes by 2-AAF is the same in Cop and F344 rats. These results show that the Cop rat is highly resistant to the chemical induction of putative preneoplastic liver foci and nodules.
- Published
- 1997
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33. Fatty acid synthase plays a role in cancer metabolism beyond providing fatty acids for phospholipid synthesis or sustaining elevations in glycolytic activity
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Richard P. Bazinet, Robin E. Duncan, Michael C. Archer, and Kathryn E. Hopperton
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Phospholipid ,chemistry.chemical_compound ,Neoplasms ,Humans ,Glycolysis ,adipocyte protein 2 ,Fatty acid synthesis ,Cells, Cultured ,Phospholipids ,chemistry.chemical_classification ,biology ,Esterification ,Lipogenesis ,Fatty Acids ,Fatty acid ,Cell Biology ,Lipid Metabolism ,Cell Hypoxia ,Fatty Acid Synthase, Type I ,Fatty acid synthase ,chemistry ,Biochemistry ,Cancer cell ,biology.protein ,MCF-7 Cells ,Female - Abstract
Fatty acid synthase is over-expressed in many cancers and its activity is required for cancer cell survival, but the role of endogenously synthesized fatty acids in cancer is unknown. It has been suggested that endogenous fatty acid synthesis is either needed to support the growth of rapidly dividing cells, or to maintain elevated glycolysis (the Warburg effect) that is characteristic of cancer cells. Here, we investigate both hypotheses. First, we compared utilization of fatty acids synthesized endogenously from (14)C-labeled acetate to those supplied exogenously as (14)C-labeled palmitate in the culture medium in human breast cancer (MCF-7 and MDA-MB-231) and untransformed breast epithelial cells (MCF-10A). We found that cancer cells do not produce fatty acids that are different from those derived from exogenous palmitate, that these fatty acids are esterified to the same lipid and phospholipid classes in the same proportions, and that their distribution within neutral lipids is not different from untransformed cells. These results suggest that endogenously synthesized fatty acids do not fulfill a specific function in cancer cells. Furthermore, we observed that cancer cells excrete endogenously synthesized fatty acids, suggesting that they are produced in excess of requirements. We next investigated whether lipogenic activity is involved in the maintenance of high glycolytic activity by culturing both cancer and non-transformed cells under anoxic conditions. Although anoxia increased glycolysis 2-3 fold, we observed no concomitant increase in lipogenesis. Our results indicate that breast cancer cells do not have a specific qualitative or quantitative requirement for endogenously synthesized fatty acids and that increased de novo lipogenesis is not required to sustain elevations in glycolytic activity induced by anoxia in these cells.
- Published
- 2013
34. SHORT COMMUNICATION: Inhibition of rat mammary tumorigenesis by dietary cholesterol
- Author
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Michael C. Archer, W. R. Bruce, and Ahmed El-Sohemy
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Cancer Research ,medicine.medical_specialty ,Mammary tumor ,Cholesterol ,Mammary gland ,General Medicine ,medicine.disease ,Lower risk ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Internal medicine ,medicine ,lipids (amino acids, peptides, and proteins) ,Breast disease ,Anticarcinogen ,Carcinogen ,Lipoprotein - Abstract
The effects of dietary cholesterol and oxidized cholesterolon mammary tumor development were examined in femaleSprague-Dawley rats exposed to the carcinogen yV-methyl-N-nitrosourea (MNU). Animals were administered50 mg/kg MNU at 50 days of age and fed either a control(AIN-76) diet or the control diet supplemented with 03%cholesterol or 03% oxidized cholesterol for up to 26weeks. The oxidized cholesterol was prepared by heatingcholesterol at 110°C for 48 h. Gas chromatographic analysisof the oxidized cholesterol revealed a 2% yield of oxidationproducts in addition to a large amount of unchangedcholesterol (>96%). Tumor incidence in the cholesterolgroup (67%) was significantly lower than in the controlgroup (96%, P
- Published
- 1996
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35. An Evaluation of the Roles of Metabolic Denitrosation and α-Hydroxylation in the Hepatotoxicity of N-Nitrosodimethylamine
- Author
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Larry K. Keefer, Michael C. Archer, and Valentia M. Lee
- Subjects
Male ,Cell Survival ,Swine ,Hydroxylation ,Toxicology ,Nitric oxide ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,N-Nitrosodimethylamine ,Animals ,Cytotoxicity ,Cells, Cultured ,L-Lactate Dehydrogenase ,Methylamine ,General Medicine ,Metabolism ,Rats ,Liver ,chemistry ,Biochemistry ,Nitrosamine ,Toxicity ,Carcinogens ,Chemical and Drug Induced Liver Injury ,Nitroso Compounds - Abstract
N-Nitrosodimethylamine (NDMA) is a potent hepatotoxic agent in rats. NDMA causes cell death that does not correlate with known mechanisms of toxicity such as the production of oxidative stress or covalent binding to proteins. The following studies were designed to determine whether NDMA cytotoxicity is the result of metabolic denitrosation or alpha-hydroxylation of the nitrosamine. We determined the toxicity of various metabolites of NDMA in monolayer cultures of primary rat hepatocytes. NDMA was toxic at 0.1 mM in our cultures, but the metabolites formaldehyde, methanol, and methylamine were not toxic at this concentration. We used diazeniumdiolates that spontaneously release nitric oxide (NO) in aqueous media to deliver NO to hepatocytes in culture. The results show that, while NO released from diazeniumdiolates causes death in hepatocytes, the levels of NO produced during NDMA metabolism are insufficient to account for the toxicity of the nitrosamine. NDMA-d6, the fully deuteriated form of NDMA that undergoes approximately twice as much denitrosation in vivo as NDMA, was significantly less cytotoxic than NDMA. In contrast, N-nitroso(acetoxymethyl)methylamine (AcO-NDMA), a stable precursor of the methanediazonium ion, was found to cause toxicity equivalent of NDMA on a molar basis. Altogether, our results with methylamine, formaldehyde, methanol, the diazeniumdiolates, and NDMA-d6 indicate that NDMA toxicity is not the result of metabolic denitrosation, while the toxicity of AcO-NDMA provides strong strong evidence that the formation of the methanediazonium ion via alpha-hydroxylation leads to cell death.
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- 1996
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36. Metabolism of N-nitrosomethylbenzylamine by microsomes from perivenous and periportal hepatocytes
- Author
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Michael C. Archer and Xiu-Yan Xie
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Guanine ,Biology ,Dimethylnitrosamine ,Rats, Sprague-Dawley ,Cytochrome P-450 Enzyme System ,Internal medicine ,medicine ,Animals ,Lobules of liver ,Gamma-glutamyltransferase ,Carcinogen ,Cytochrome P450 ,Cytochrome P-450 CYP2E1 ,Oxidoreductases, N-Demethylating ,gamma-Glutamyltransferase ,Metabolism ,biology.organism_classification ,Rats ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Microsoma ,Hepatocyte ,Carcinogens ,Microsomes, Liver ,biology.protein ,Microsome - Abstract
Immunohistochemical studies have shown the presence of O6-methylguanine in the perivenous area but not the periportal area of the liver lobule following administration of N-nitrosomethylbenzylamine (NMBzA) to rats. This study was designed to investigate the hypothesis that hepatic heterogeneity of NMBzA metabolism determines the distribution of O6-methylguanine in the liver. Using microsomes prepared from purified perivenous and periportal hepatocytes, we showed that NMBzA debenzylase and demethylase activities were 2-fold and 1.5-fold higher, respectively, in perivenous than in periportal microsomes. Our results suggest that the combined effect of a higher rate of formation and lower rate of repair of O6-methylguanine in perivenous than in periportal hepatocytes could explain the localization of this base in zone 3 of the liver lobule following NMBzA treatment.
- Published
- 1994
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37. Inhibition of fatty acid synthase and Sp1 expression by 3,3'-diindolylmethane in human breast cancer cells
- Author
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George E Saati and Michael C. Archer
- Subjects
Cancer Research ,3,3'-Diindolylmethane ,Indoles ,Time Factors ,Sp1 Transcription Factor ,Medicine (miscellaneous) ,Diindolylmethane ,Breast Neoplasms ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Anticarcinogenic Agents ,Humans ,Cell Proliferation ,Sp1 transcription factor ,Nutrition and Dietetics ,biology ,Osmolar Concentration ,Cancer ,medicine.disease ,Neoplasm Proteins ,Fatty Acid Synthase, Type I ,Fatty acid synthase ,Oncology ,chemistry ,Biochemistry ,Cell culture ,Cancer cell ,Lipogenesis ,Cancer research ,biology.protein ,Female - Abstract
The putative cancer preventive agent 3,3'-diindolylmethane (DIM) is formed in the acidic environment of the stomach following consumption of indole-3-carbinol (I3C), which is present in vegetables of the Brassica genus. We have recently shown that the transcription factor Sp1 is involved in the regulation of both proliferation and de novo lipogenesis in cancer cells. Here we show that DIM inhibits the proliferation of 3 human breast cancer cell lines, MCF-7, MDA-MB-231, and SKBr-3, and concomitantly inhibits the expression of Sp1 and fatty acid synthase (FAS). There were no DIM-related effects on the proliferation or expression of Sp1 or FAS in the nontumorigenic human breast epithelial cell line MCF-10A. These results suggest that inhibition of Sp1 and/or FAS expression could contribute to the anticancer properties of the dietary indoles.
- Published
- 2011
38. Diet, aberrant crypt foci and colorectal cancer
- Author
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W. Robert Bruce, Denis E. Corpet, Michael C. Archer, Alan Medline, Salomon Minkin, Ya Yin, Dennis Stamp, and Xue-Ming Zhang
- Subjects
Oncology ,Intervention trials ,medicine.medical_specialty ,Carcinogenicity Tests ,Colorectal cancer ,Health, Toxicology and Mutagenesis ,Rectum ,Dietary factors ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Epidemiology ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,business.industry ,medicine.disease ,Diet ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Colorectal Neoplasms ,Carcinogenesis ,business ,Rectal disease ,Aberrant crypt foci - Abstract
We have used the aberrant crypt focus (ACF) assay to test and develop hypotheses linking diet and colon cancer. The hypotheses were suggested by epidemiological studies that identified possible dietary factors associated with colorectal cancer risk. The ACF assay was used to quantitate the effect of the dietary factors on the initiation and growth of these putative precursors of colon cancers in experimental animals. Using this approach we have developed 3 new hypotheses for the role of diet in colorectal cancer. These are (1) a risk associated with 5-hydroxymethyl-2-furaldehyde in caramelized sugar, (2) a risk associated with some factor in thermolyzed casein, and (3) a risk associated with single nutrient boluses of sucrose and fructose. The importance of these hypotheses has still to be tested in long term carcinogenesis experiments, in analytic epidemiology studies and then, perhaps, in intervention trials.
- Published
- 1993
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39. Evidence that the hepatotoxicity of N-nitrosodimethylamine in the rat is unrelated to DNA methylation
- Author
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Valentia M. Lee, Wei Chin, and Michael C. Archer
- Subjects
Male ,Pharmacology ,Toxicology ,Methylation ,Dimethylnitrosamine ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,N-Nitrosodimethylamine ,medicine ,Animals ,Carcinogen ,Dose-Response Relationship, Drug ,Chemistry ,Methylnitrosourea ,DNA ,General Medicine ,Metabolism ,Rats ,Drug Combinations ,Dose–response relationship ,medicine.anatomical_structure ,Liver ,Mechanism of action ,Biochemistry ,Nitrosamine ,Hepatocyte ,Toxicity ,Carcinogens ,medicine.symptom - Abstract
N-Nitrosodimethylamine (NDMA) is a potent hepatotoxicant in the rat, but the mechanism by which it lethally injures hepatocytes is not known. NDMA is metabolized in the liver to the methanediazonium ion that methylates hepatic DNA. Neither N-nitrosomethylbenzylamine (NMBzA) nor methylnitrosourea (MNU) produces liver tumors, but via metabolism in the case of NMBzA, or via spontaneous decomposition at physiological pH in the case of MNU, both compounds produce the methanediazonium ion and methylate hepatic DNA. Here we have compared quantitatively the ability of NDMA, NMBzA, and MNU to cause lethal injury to hepatocytes in vivo and to produce O6-methylguanine in hepatic DNA. Neither NMBzA nor MNU produced hepatotoxicity in the rat even at doses as high as 667 mumol/kg body wt for NMBzA and 971 mumol/kg body wt for MNU. NMBzA given at the same time as NDMA potentiated the hepatotoxicity of NDMA, but O6-methylguanine levels were only additive. MNU did not potentiate the hepatotoxicity of NDMA, but again, the O6-methylguanine levels were additive when NDMA and MNU were administered together. These results appear to rule out the involvement of DNA methylation in lethal hepatocyte injury by NDMA.
- Published
- 1993
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40. The role of hepatocyte heterogeneity in the initiation of hepatocarcinogenesis
- Author
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Ross G. Cameron, Valentia M. Lee, and Michael C. Archer
- Subjects
Male ,Cancer Research ,Cell division ,Tumor initiation ,Biology ,medicine.disease_cause ,Dimethylnitrosamine ,Rats, Sprague-Dawley ,Liver Neoplasms, Experimental ,medicine ,Animals ,Lobules of liver ,Carcinogen ,Glutathione Transferase ,Cell growth ,General Medicine ,Immunohistochemistry ,Molecular biology ,Rats ,medicine.anatomical_structure ,Liver ,Biochemistry ,Enzyme Induction ,Hepatocyte ,DNA methylation ,Carcinogens ,Carcinogenesis ,Cell Division ,DNA Damage ,Nitroso Compounds - Abstract
N-Nitrosodimethylamine (NDMA) is a carcinogen in rat liver while N-nitrosomethylbenzylamine (NMBzA) produces no liver tumors but is a potent esophageal carcinogen in the rat. Both nitrosamines, however, are metabolically activated in the liver and methylate hepatic DNA. The reasons for their different carcinogenic properties in rat liver are unclear. Here we show that as expected, NDMA produces large numbers of putative initiated hepatocytes that overexpress the placental form of glutathione S-transferase (GST-P+ hepatocytes). Hepatocyte division induced by the hepatotoxic effect of NDMA occurs principally in the periportal region of the liver lobule, while O6-methylguanine formation is principally in the DNA of perivenous cells. These two effects lead to the production of GST-P+ hepatocytes in roughly equal numbers throughout the liver lobule. NMBzA also induces the formation of a small, but significant number of GST-P+ hepatocytes. The NMBzA-induced GST-P+ hepatocytes are localized within the perivenous zone of the liver lobule. Since, unlike NDMA, NMBzA produces no hepatocellular necrosis and hence does not induce regenerative cell division, these results suggest that NMBzA initiates only those hepatocytes adjacent to the hepatic vein that are spontaneously dividing at the time their DNA becomes methylated by the nitrosamine. We used partial hepatectomy to stimulate cell division in specific regions of the liver lobule. When the peak of DNA methylation produced by NMBzA in the perivenous cells coincided with a peak of cell division in that region, an increased number of GST-P+ hepatocytes was induced. Our results suggest that the potency of initiating agents in the liver depends both on their ability to form mutagenic lesions in DNA and to induce division in the specific hepatocytes that contain the modified DNA.
- Published
- 1993
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41. The effect of physiological concentrations of sex hormones, insulin, and glucagon on growth of breast and prostate cells supplemented with unmodified human serum
- Author
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Balachandran Bashyam, Amin Esfahani, David J.A. Jenkins, Cyril W.C. Kendall, and Michael C. Archer
- Subjects
Male ,Serum ,medicine.medical_specialty ,medicine.medical_treatment ,Cell Culture Techniques ,Breast Neoplasms ,Biology ,Glucagon ,Internal medicine ,Cell Line, Tumor ,LNCaP ,medicine ,Humans ,Insulin ,skin and connective tissue diseases ,Gonadal Steroid Hormones ,Testosterone ,Cell Proliferation ,Analysis of Variance ,Cell growth ,Prostatic Neoplasms ,Cell Biology ,General Medicine ,Culture Media ,Endocrinology ,Dihydrotestosterone ,Female ,hormones, hormone substitutes, and hormone antagonists ,Fetal bovine serum ,Developmental Biology ,Hormone ,medicine.drug - Abstract
The majority of cell culture studies have assessed the effect of hormones on cancer cell growth using media supplemented with charcoal-treated fetal bovine serum (CTS). We aimed to determine whether using a system more reflective of the human condition by changing the charcoal-treated serum to an untreated pooled human serum (PHS) resulted in the same hormone responses in breast and prostate cell lines. MCF-7 breast cancer, MCF-10A non-transformed breast, and LNCaP prostate cancer cell lines supplemented with PHS were treated with high and low physiological concentrations of six hormones (17β-estradiol, dehydroepiandosterone (DHEA), dihydrotestosterone (DHT), testosterone, insulin, and glucagon). Cell growth was measured after 72 h of incubation. All hormones stimulated growth of MCF-7 cells (p
- Published
- 2010
42. Reproducibility in growth of breast and prostate cells stimulated with serum taken at different points in time from individuals on their habitual diets
- Author
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David J.A. Jenkins, Amin Esfahani, Balachandran Bashyam, Michael C. Archer, Korbua Srichaikul, and Cyril W.C. Kendall
- Subjects
Reproducibility ,medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Genetics ,medicine ,business ,Molecular Biology ,Biochemistry ,Biotechnology ,Prostate cells - Published
- 2010
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43. The effect of physiological concentrations of six hormones on the growth of breast and prostate cell lines treated with human serum
- Author
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David J.A. Jenkins, Balachandran Bashyam, Cyril W.C. Kendall, Michael C. Archer, Korbua Srichaikul, and Amin Esfahani
- Subjects
medicine.medical_specialty ,Endocrinology ,Prostate cell ,business.industry ,Internal medicine ,Genetics ,medicine ,business ,Molecular Biology ,Biochemistry ,Biotechnology ,Hormone - Published
- 2010
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44. The 10t,12c isomer of conjugated linoleic acid inhibits fatty acid synthase expression and enzyme activity in human breast, colon, and prostate cancer cells
- Author
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Michael C. Archer and Dominic Lau
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Linoleic acid ,Conjugated linoleic acid ,Medicine (miscellaneous) ,Gene Expression ,Antineoplastic Agents ,Breast Neoplasms ,chemistry.chemical_compound ,Isomerism ,Internal medicine ,Cell Line, Tumor ,LNCaP ,Medicine ,Humans ,Linoleic Acids, Conjugated ,Enzyme Inhibitors ,chemistry.chemical_classification ,Nutrition and Dietetics ,biology ,business.industry ,Prostatic Neoplasms ,Molecular biology ,Enzyme assay ,Fatty acid synthase ,Enzyme ,Endocrinology ,Oncology ,chemistry ,Cancer cell ,Colonic Neoplasms ,biology.protein ,Growth inhibition ,Fatty Acid Synthases ,business ,HT29 Cells ,Cell Division - Abstract
The objective of this study was to determine whether downregulation of fatty acid synthase (FAS) expression and/or inhibition of its activity by the two major CLA isomers, 10t,12c and 9c,11t CLA, could contribute to their inhibitory effect on the growth of human breast (MCF-7), colon (HT-29) and prostate (LNCaP) cancer cell lines. We first confirmed and extended the results of others showing that the inhibitory action of CLA on proliferation is dependent on the cell type as well as the structure of the isomer, the 10,12 isomer being a more potent inhibitor than the 9,11 isomer in the concentration range 25-100 microM. By Western analysis, we showed that 10,12 CLA downregulated FAS expression in all of the cell lines in a concentration-dependent manner, but the 9,11 isomer had no effect. Both isomers inhibited FAS enzyme activity, but 10,12 CLA was again more potent than the 9,11 isomer. Our results suggest that downregulation of FAS by 10,12 CLA, but not by the 9,11 isomer, as well as inhibition of FAS enzyme activity by both isomers, may contribute to growth inhibition of cancer cells but only at relatively high concentrations.
- Published
- 2010
45. Formation and repair of O6-methylguanine and methylation of the Ha-ras proto-oncogene by N-methyl-N-nitrosourea are not associated with mammary tumor resistance in the Copenhagen rat
- Author
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Shi-Jiang Lu, Michael C. Archer, and E. J. Chaulk
- Subjects
Cancer Research ,medicine.medical_specialty ,Guanine ,DNA Repair ,Mammary gland ,Drug Resistance ,Biology ,medicine.disease_cause ,Methylation ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Gene ,Carcinogen ,Mammary tumor ,Oncogene ,Mammary Neoplasms, Experimental ,Methylnitrosourea ,DNA, Neoplasm ,General Medicine ,Blotting, Northern ,Molecular biology ,Rats ,Blotting, Southern ,Genes, ras ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Female ,Carcinogenesis ,DNA - Abstract
A high incidence of mammary adenocarcinomas is induced in sexually immature, female Buf/N rats by a single dose of N-methyl-N-nitrosourea (MNU). The Ha-ras gene is activated in a majority of these tumors. The Copenhagen (Cop) rat is completely resistant to mammary gland carcinogenesis by a number of carcinogens, including MNU. Here we show that MNU-treated Buf/N and Cop rats do not differ in the extent of formation and rate of repair of O6-methylguanine in DNA isolated from their mammary epithelial cells. Furthermore, we show that the transcriptional activities of the Ha-ras genes are similar in the mammary glands of Buf/N and Cop rats and that the extents of methylation by MNU of restriction fragments containing the Ha-ras gene from mammary gland DNA are not different for the two strains. Resistance of the Cop rat to mammary carcinogenesis, therefore, appears not to be due to a defect in the interaction of the carcinogen with the target DNA.
- Published
- 1992
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46. ras Oncogene activation in mammary carcinomas induced byn-methyl-n-nitrosourea in copenhagen rats
- Author
-
Michael C. Archer and Shi-Jiang Lu
- Subjects
Cancer Research ,medicine.medical_specialty ,Adenosquamous carcinoma ,Molecular Sequence Data ,Mammary gland ,Tumor initiation ,Adenocarcinoma ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,Internal medicine ,medicine ,Animals ,Electrophoretic mobility shift assay ,Rats, Inbred BUF ,Molecular Biology ,Gene ,Carcinogen ,Mutation ,Base Sequence ,Mammary Neoplasms, Experimental ,Methylnitrosourea ,Rats, Inbred Strains ,DNA, Neoplasm ,medicine.disease ,Molecular biology ,Rats ,Gene Expression Regulation, Neoplastic ,Genes, ras ,Endocrinology ,medicine.anatomical_structure ,Oligodeoxyribonucleotides ,Mutagenesis ,Carcinoma, Squamous Cell ,Female - Abstract
The occurrence of Ha-ras and Ki-ras oncogenes was investigated in mammary tumors produced by treating genetically resistant Copenhagen (Cop) rats with N-methyl-N-nitrosourea. G35-->A codon 12 mutations in both Ha-ras and Ki-ras genes were analyzed by a polymerase chain reaction/liquid hybridization and gel retardation assay. More than half of the adenocarcinomas analyzed contained an activated Ha-ras gene. This was also the predominant mutation in similar tumors from susceptible Buf/N rats, suggesting a common mechanism of initiation. In contrast, only two of 15 mammary adenosquamous carcinomas from the Cop rats contained an activated Ha-ras gene, suggesting a different initiation mechanism for most of these tumors. Ki-ras activation was found in none of five and one of five adenocarcinomas from Buf/N and Cop rats, respectively, and in none of 13 adenosquamous carcinomas from Cop rats. These results suggest that Ki-ras activation does not play a major role in the initiation of the mammary tumors.
- Published
- 1992
- Full Text
- View/download PDF
47. Ezetimibe reverses the inhibitory effects of dietary cholesterol on mammary tumorigenesis in rats
- Author
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Michael C. Archer and Erin McNamara
- Subjects
Cancer Research ,medicine.medical_specialty ,Absorption (skin) ,Biology ,Inhibitory postsynaptic potential ,Cholesterol, Dietary ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Ezetimibe ,Internal medicine ,Mammary tumorigenesis ,medicine ,Animals ,In patient ,Tumor multiplicity ,Cholesterol ,Anticholesteremic Agents ,Mammary Neoplasms, Experimental ,Methylnitrosourea ,Rats ,Endocrinology ,Oncology ,chemistry ,Carcinogens ,Azetidines ,lipids (amino acids, peptides, and proteins) ,Female ,Dietary Cholesterol ,medicine.drug - Abstract
There are concerns regarding increased cancer incidence in patients treated with ezetimibe, an inhibitor of the absorption of dietary cholesterol. Here we tested the hypothesis that ezetimibe will accelerate mammary tumorigenesis in rats. The drug was administered at a dose of 1 ppm in an AIN-93G diet that contained 0.3% cholesterol. This experimental diet and control diets that contained either no additions or cholesterol or ezetimibe only, were fed to groups of 30 Sprague-Dawley rats 3 days after they were treated with 50 mg/kg methylnitrosourea (MNU). All rats were euthanized 22 weeks after MNU administration. Tumor multiplicity was significantly smaller in rats fed cholesterol than those fed no cholesterol (1.84 +/- 0.42 vs. 3.86 +/- 0.86 respectively, P0.05), but was significantly greater in the cholesterol/ezetimibe group than the group fed only cholesterol (3.48 +/- 0.59 vs. 1.84 +/- 0.42 respectively, P0.04). The average weight of tumors/rat was also significantly larger in the cholesterol/ezetimibe group than those fed cholesterol alone (5.67 +/- 1.15 vs. 2.56 +/- 0.71 respectively, P0.04). As expected, ezetimibe prevented the cholesterol raising effect of the dietary cholesterol. These results show that ezetimibe reverses the inhibitory effect of dietary cholesterol on the development of rat mammary tumors.
- Published
- 2009
48. Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells
- Author
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Michael C. Archer and Suying Lu
- Subjects
Cancer Research ,Chromatin Immunoprecipitation ,Sp1 Transcription Factor ,Blotting, Western ,Sp4 Transcription Factor ,Biology ,Transfection ,RNA interference ,Cell Line, Tumor ,Neoplasms ,Gene expression ,Humans ,cdc25 Phosphatases ,RNA, Small Interfering ,Promoter Regions, Genetic ,Transcription factor ,Cell Proliferation ,Regulation of gene expression ,Antibiotics, Antineoplastic ,Reverse Transcriptase Polymerase Chain Reaction ,Lipogenesis ,Promoter ,Estrogens ,Plicamycin ,HCT116 Cells ,Molecular biology ,Cell biology ,Gene Expression Regulation, Neoplastic ,Sp3 Transcription Factor ,Oncology ,Cancer cell ,Fatty Acid Synthases ,Sterol Regulatory Element Binding Protein 1 ,Chromatin immunoprecipitation ,Protein Binding - Abstract
Cancers express high levels of fatty acid synthase (FAS) from which they derive fatty acids for membrane biosynthesis to sustain cell proliferation. How cancer cells coordinate de novo lipogenesis and proliferation has not been investigated. Transcription factors Sp1, Sp3 and Sp4 are overexpressed in a variety of cancers and regulate gene expression by interacting with GC-rich Sp1 binding sites. Genes encoding FAS and cell cycle proteins such as CDC25A contain Sp1 binding sites in their promoters. We demonstrate by RNA interference that Sp1, Sp3 and Sp4 all play a role in regulating CDC25A expression and proliferation in human breast cancer cells. Only Sp1, however, also regulates FAS. Furthermore, mithramycin, which blocks Sp1 binding sites, decreased proliferation, inhibited CDC25A and FAS expression and reduced binding of Sp1 to the promoters of these genes as assessed by ChIP assays. Conversely, 17beta-estradiol (E(2)) increased proliferation and CDC25A and FAS expression along with increased binding of Sp1 to the promoters of the 2 genes. In addition, we showed that the expression of sterol regulatory element-binding protein-1c (SREBP-1c), the only transcription factor that has been shown to regulate genes of lipogenic enzymes in cancer cells, is also regulated by Sp1. Finally, we demonstrated that Sp1 plays a role in sustaining proliferation and FAS expression in colon as well as prostate cancer cells. Overall, these observations suggest that Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells.
- Published
- 2009
49. Fatty acid synthase is over-expressed in large aberrant crypt foci in rats treated with azoxymethane
- Author
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Michael C. Archer and Dominic Lau
- Subjects
Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Colorectal cancer ,Azoxymethane ,Biology ,medicine.disease_cause ,digestive system ,chemistry.chemical_compound ,medicine ,Animals ,Nuclear atypia ,Cell Nucleus ,Cancer ,medicine.disease ,Immunohistochemistry ,digestive system diseases ,Rats, Inbred F344 ,Rats ,Fatty acid synthase ,Oncology ,chemistry ,Dysplasia ,Colonic Neoplasms ,biology.protein ,Fatty Acid Synthases ,Carcinogenesis ,Precancerous Conditions ,Aberrant crypt foci - Abstract
Fatty acid synthase (FAS) is over-expressed in many human cancers including colon. High levels of FAS expression have also been observed in a number of lesions that are precursors to invasive colorectal cancer. However, FAS expression in aberrant crypt foci (ACF), the earliest identifiable lesions in colon cancer development, has not been investigated. In this study, we treated Fisher rats with a single dose of the colon carcinogen azoxymethane then evaluated ACF 100 days later. We showed that large ACF (≥4 crypts/focus) have a significantly higher level of immunohistochemical staining for FAS than either small ACF (≤3 crypts/focus) or normal crypts. Furthermore, the severity of nuclear atypia in ACF was positively associated with increased expression of FAS. These findings suggest that the genes associated with FAS over-expression are activated early in the stepwise development of colon cancer, though not until the ACF have reached a critical size with a level of nuclear atypia indicative of dysplasia. © 2008 Wiley-Liss, Inc.
- Published
- 2009
50. Selective cytotoxicity of N-nitrosamines to cultured rat esophageal epithelial cells
- Author
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A. Giles, Peter F. Zucker, Michael C. Archer, and E. J. Chaulk
- Subjects
Male ,Cancer Research ,Nitrosamines ,Cell Survival ,Tetrazolium Salts ,Cell Count ,Biology ,Epithelium ,Dimethylnitrosamine ,chemistry.chemical_compound ,Esophagus ,medicine ,Animals ,Cytotoxic T cell ,Dimethyl Sulfoxide ,Cytotoxicity ,Cells, Cultured ,Carcinogen ,Dose-Response Relationship, Drug ,Epithelial Cells ,Trypan Blue ,General Medicine ,Esophageal cancer ,medicine.disease ,Rats ,Thiazoles ,Cell killing ,medicine.anatomical_structure ,chemistry ,Cell culture ,Nitrosamine ,Immunology ,Carcinogens ,Cancer research - Abstract
The rat esophageal carcinogen N-nitrosomethylbenzylamine was shown to be highly toxic to rat esophageal epithelial (REE) cells in short-term primary culture. A significant level of cell killing could be observed at 10(-6) M. Several other esophageal carcinogens were also cytotoxic in a dose-dependent manner. Nitrosamines that do not produce esophageal tumors in the rat were generally unable to kill the esophageal cells. The results demonstrate that REE cells retain their metabolic capacity to activate specific nitrosamines to toxic metabolites. The culture system will be useful for mechanistic studies on the tissue specificity of these carcinogens, as well as to search for environmental agents that kill esophageal cells that may be involved in the causation of esophageal cancer.
- Published
- 1991
- Full Text
- View/download PDF
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