33 results on '"Sally Gaddis"'
Search Results
2. Supplementary Table S1 from Breast Cancer Molecular Signatures as Determined by SAGE: Correlation with Lymph Node Status
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C. Marcelo Aldaz, Aysegul Sahin, Steve Horvath, Tao Shi, Sally Gaddis, Maria I. Nunez, Yuhui Hu, Jeffrey A. Drake, Kathleen A. Hawkins, Hongxia Sun, and Martín C. Abba
- Abstract
Supplementary Table S1 from Breast Cancer Molecular Signatures as Determined by SAGE: Correlation with Lymph Node Status
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- 2023
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3. Supplementary Materials 1 from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
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C. Marcelo Aldaz, Daniel Medina, Powel H. Brown, Reid P. Bissonnette, Jamal Hill, Frances S. Kittrell, Sally Gaddis, Carla C. Levy, Yuhui Hu, and Martín C. Abba
- Abstract
Supplementary Materials 1 from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
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- 2023
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4. Supplementary Materials 3 from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
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C. Marcelo Aldaz, Daniel Medina, Powel H. Brown, Reid P. Bissonnette, Jamal Hill, Frances S. Kittrell, Sally Gaddis, Carla C. Levy, Yuhui Hu, and Martín C. Abba
- Abstract
Supplementary Materials 3 from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
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- 2023
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5. Data from Breast Cancer Molecular Signatures as Determined by SAGE: Correlation with Lymph Node Status
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C. Marcelo Aldaz, Aysegul Sahin, Steve Horvath, Tao Shi, Sally Gaddis, Maria I. Nunez, Yuhui Hu, Jeffrey A. Drake, Kathleen A. Hawkins, Hongxia Sun, and Martín C. Abba
- Abstract
Global gene expression measured by DNA microarray platforms have been extensively used to classify breast carcinomas correlating with clinical characteristics, including outcome. We generated a breast cancer Serial Analysis of Gene Expression (SAGE) high-resolution database of ∼2.7 million tags to perform unsupervised statistical analyses to obtain the molecular classification of breast-invasive ductal carcinomas in correlation with clinicopathologic features. Unsupervised statistical analysis by means of a random forest approach identified two main clusters of breast carcinomas, which differed in their lymph node status (P = 0.01); this suggested that lymph node status leads to globally distinct expression profiles. A total of 245 (55 up-modulated and 190 down-modulated) transcripts were differentially expressed between lymph node (+) and lymph node (−) primary breast tumors (fold change, ≥2; P < 0.05). Various lymph node (+) up-modulated transcripts were validated in independent sets of human breast tumors by means of real-time reverse transcription-PCR (RT-PCR). We validated significant overexpression of transcripts for HOXC10 (P = 0.001), TPD52L1 (P = 0.007), ZFP36L1 (P = 0.011), PLINP1 (P = 0.013), DCTN3 (P = 0.025), DEK (P = 0.031), and CSNK1D (P = 0.04) in lymph node (+) breast carcinomas. Moreover, the DCTN3 (P = 0.022) and RHBDD2 (P = 0.002) transcripts were confirmed to be overexpressed in tumors that recurred within 6 years of follow-up by real-time RT-PCR. In addition, meta-analysis was used to compare SAGE data associated with lymph node (+) status with publicly available breast cancer DNA microarray data sets. We have generated evidence indicating that the pattern of gene expression in primary breast cancers at the time of surgical removal could discriminate those tumors with lymph node metastatic involvement using SAGE to identify specific transcripts that behave as predictors of recurrence as well. (Mol Cancer Res 2007;5(9):881–90)
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- 2023
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6. Related Article from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
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C. Marcelo Aldaz, Daniel Medina, Powel H. Brown, Reid P. Bissonnette, Jamal Hill, Frances S. Kittrell, Sally Gaddis, Carla C. Levy, Yuhui Hu, and Martín C. Abba
- Abstract
Related Article from Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
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- 2023
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7. Supplementary Table S2 from A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
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C. Marcelo Aldaz, Aysegul A. Sahin, Marcos R. Estecio, Jianjun Shen, Sally Gaddis, Yoko Takata, Matias Butti, Ezequiel Lacunza, Yi Zhong, Jaeho Lee, Yue Lu, Ting Gong, and Martin C. Abba
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Supplementary Table S2: List of mutated genes, Indels and Copy number variations detected in DCIS samples.
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- 2023
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8. Data from From Mice to Humans
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C. Marcelo Aldaz, Daniel Medina, Keith Baggerly, Aysegul Sahin, Sally Gaddis, Li Deng, Martin C. Abba, Frances Kittrell, Jeffrey Drake, Hongxia Sun, and Yuhui Hu
- Abstract
Genetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (>300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (>2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBα), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets.This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
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- 2023
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9. Supplementary Table and Figure Legends from A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
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C. Marcelo Aldaz, Aysegul A. Sahin, Marcos R. Estecio, Jianjun Shen, Sally Gaddis, Yoko Takata, Matias Butti, Ezequiel Lacunza, Yi Zhong, Jaeho Lee, Yue Lu, Ting Gong, and Martin C. Abba
- Abstract
Supplementary Table and Figure Legends: Legend for Supplementary Tables S1-S5 and Supplementary Figures S1-S4.
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- 2023
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10. Supplementary Figure S3 from A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
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C. Marcelo Aldaz, Aysegul A. Sahin, Marcos R. Estecio, Jianjun Shen, Sally Gaddis, Yoko Takata, Matias Butti, Ezequiel Lacunza, Yi Zhong, Jaeho Lee, Yue Lu, Ting Gong, and Martin C. Abba
- Abstract
Supplementary Figure S3: TP53 pathway activity in invasive breast carcinomas from the TCGA-BRCA dataset.
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- 2023
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11. Supplementary Table 3 from From Mice to Humans
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C. Marcelo Aldaz, Daniel Medina, Keith Baggerly, Aysegul Sahin, Sally Gaddis, Li Deng, Martin C. Abba, Frances Kittrell, Jeffrey Drake, Hongxia Sun, and Yuhui Hu
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Supplementary Table 3 from From Mice to Humans
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- 2023
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12. Supplementary Table 1 from From Mice to Humans
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C. Marcelo Aldaz, Daniel Medina, Keith Baggerly, Aysegul Sahin, Sally Gaddis, Li Deng, Martin C. Abba, Frances Kittrell, Jeffrey Drake, Hongxia Sun, and Yuhui Hu
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Supplementary Table 1 from From Mice to Humans
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- 2023
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13. Supplementary Table 2 from From Mice to Humans
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C. Marcelo Aldaz, Daniel Medina, Keith Baggerly, Aysegul Sahin, Sally Gaddis, Li Deng, Martin C. Abba, Frances Kittrell, Jeffrey Drake, Hongxia Sun, and Yuhui Hu
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Supplementary Table 2 from From Mice to Humans
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- 2023
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14. ATF3-Induced Mammary Tumors Exhibit Molecular Features of Human Basal-Like Breast Cancer
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Sally Gaddis, Yi Zhong, Yue Lu, Jianjun Shen, Melissa S. Simper, Michael C. MacLeod, Kevin Lin, Michelle Byrom, Leqin Yan, John Repass, Luis Della Coletta, Katherine Leslie Powell, Bin Liu, and Yueping Chen
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0301 basic medicine ,medicine.disease_cause ,basal-like ,lcsh:Chemistry ,Mice ,0302 clinical medicine ,ATF3 ,RNA-Seq ,lcsh:QH301-705.5 ,Wnt Signaling Pathway ,Spectroscopy ,Mammary tumor ,Wnt signaling pathway ,General Medicine ,Computer Science Applications ,Up-Regulation ,Mir143 ,Gene Expression Regulation, Neoplastic ,KLF4 ,030220 oncology & carcinogenesis ,Female ,KRAS ,mouse model ,Breast Neoplasms ,Mammary Neoplasms, Animal ,Biology ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Kruppel-Like Factor 4 ,breast cancer ,SOX2 ,Cell Line, Tumor ,microRNA ,medicine ,Animals ,Humans ,Mir145 ,Physical and Theoretical Chemistry ,Molecular Biology ,miRNA ,Activating Transcription Factor 3 ,Oncogene ,Organic Chemistry ,Cancer ,Mammary Neoplasms, Experimental ,medicine.disease ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cancer research - Abstract
Basal-like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem-cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. ATF3 is a potent oncogene that is aberrantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of ATF3 in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/β-catenin signaling pathway. Here, we used RNA-Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3-derived mammary tumors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of Rb1, Esr1, and Pgr and increased expression of Erbb2, Egfr, and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of Mir145 and Mir143, leading to the upregulation of their target genes including both the pluripotency factors Klf4 and Sox2 as well as the cancer stem-cell-related gene Kras. Finally, we show through knock-down experiments that ATF3 may directly modulate MIR145/143 expression. Taken together, our results indicate that the ATF3 mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.
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- 2021
15. DNMT3L facilitates DNA methylation partly by maintaining DNMT3A stability in mouse embryonic stem cells
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Hongbo Zhao, Mary W. Tomida, Marcos R. Estecio, Jianjun Shen, Sally Gaddis, Nicolas Veland, Yang Zeng, Yoko Takata, Debapriya Saha, Humaira Gowher, Kevin Lin, Yue Lu, Taiping Chen, Swanand Hardikar, and Bigang Liu
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Gene isoform ,endocrine system ,DNMT3B ,DNMT3A Gene ,Regulator ,Embryonic Development ,Biology ,DNA Methyltransferase 3A ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Enzyme Stability ,Genetics ,Animals ,DNA (Cytosine-5-)-Methyltransferases ,030304 developmental biology ,0303 health sciences ,urogenital system ,Gene regulation, Chromatin and Epigenetics ,Mouse Embryonic Stem Cells ,Methylation ,DNA Methylation ,Embryonic stem cell ,Cell biology ,DNA methylation ,embryonic structures ,030217 neurology & neurosurgery ,Protein Binding - Abstract
DNMT3L (DNMT3-like), a member of the DNMT3 family, has no DNA methyltransferase activity but regulates de novo DNA methylation. While biochemical studies show that DNMT3L is capable of interacting with both DNMT3A and DNMT3B and stimulating their enzymatic activities, genetic evidence suggests that DNMT3L is essential for DNMT3A-mediated de novo methylation in germ cells but is dispensable for de novo methylation during embryogenesis, which is mainly mediated by DNMT3B. How DNMT3L regulates DNA methylation and what determines its functional specificity are not well understood. Here we show that DNMT3L-deficient mouse embryonic stem cells (mESCs) exhibit downregulation of DNMT3A, especially DNMT3A2, the predominant DNMT3A isoform in mESCs. DNA methylation analysis of DNMT3L-deficient mESCs reveals hypomethylation at many DNMT3A target regions. These results confirm that DNMT3L is a positive regulator of DNA methylation, contrary to a previous report that, in mESCs, DNMT3L regulates DNA methylation positively or negatively, depending on genomic regions. Mechanistically, DNMT3L forms a complex with DNMT3A2 and prevents DNMT3A2 from being degraded. Restoring the DNMT3A protein level in DNMT3L-deficient mESCs partially recovers DNA methylation. Thus, our work uncovers a role for DNMT3L in maintaining DNMT3A stability, which contributes to the effect of DNMT3L on DNMT3A-dependent DNA methylation.
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- 2018
16. Genome-wide analysis of the rat colon reveals proximal-distal differences in histone modifications and proto-oncogene expression
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Sally Gaddis, Kranti Konganti, Karen Triff, Beiyan Zhou, Ivan Ivanov, and Robert S. Chapkin
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Male ,Base Sequence ,Colon ,Physiology ,Biology ,Molecular biology ,Rats ,Chromatin ,Histones ,Rats, Sprague-Dawley ,Histone ,Proto-Oncogene Proteins ,Gene expression ,Genetics ,Transcriptional regulation ,biology.protein ,Animals ,H3K4me3 ,Epigenetics ,Call for Papers: Epigenetics and Epigenomics ,Chromatin immunoprecipitation ,Gene ,DNA Primers ,Genome-Wide Association Study - Abstract
Since disease susceptibility of the intestine exhibits an anatomical bias, we propose that the chromatin landscape, especially the site-specific epigenetic differences in histone modification patterns throughout the colonic longitudinal axis, contributes to the differential incidence of site-specific pathology. To test this hypothesis, we assessed the chromatin structure associated with gene expression profiles in the rat proximal and distal colon by globally correlating chromatin immunoprecipitation next-generation sequencing analysis (ChIP-Seq) with mRNA transcription (RNA-Seq) data. Crypts were isolated from the proximal and distal colonic regions from rats maintained on a semipurified diet, and mRNA gene expression profiles were generated by RNA-Seq. The remaining isolated crypts were formaldehyde-cross-linked and chromatin immunoprecipitated with antibodies against H3K4me3, H3K9me3, and RNA polymerase II. Globally, RNA-Seq results indicate that 9,866 genes were actively expressed, of which 540 genes were differentially expressed between the proximal and distal colon. Gene ontology analysis indicates that crypt location significantly affected both chromatin and transcriptional regulation of genes involved in enterocyte movement, lipid metabolism, lymphatic development, and immune cell trafficking. Gene function analysis indicates that the PI3-kinase signaling pathway was regulated in a site-specific manner, e.g., proto-oncogenes, JUN, FOS, and ATF, were upregulated in the distal colon. Middle and long noncoding RNAs (lncRNAs) were also detected in the colon, including select lncRNAs formerly only detected in the rat nervous system. In summary, distinct combinatorial patterns of histone modifications exist in the proximal versus distal colon. These site-specific differences may explain the differential effects of chemoprotective agents on cell transformation in the ascending (proximal) and descending (distal) colon.
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- 2013
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17. Methods to detect replication-dependent and replication-independent DNA structure-induced genetic instability
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Sally Gaddis, Guliang Wang, and Karen M. Vasquez
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DNA Replication ,Genome instability ,Computational biology ,Biology ,medicine.disease_cause ,Instability ,Genome ,Article ,Genomic Instability ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,medicine ,Electrophoresis, Gel, Two-Dimensional ,Molecular Biology ,Genetics ,Internet ,Mutation ,Mutagenesis ,DNA replication ,Computational Biology ,Replication (computing) ,Search Engine ,Genetic Techniques ,chemistry ,Nucleic Acid Conformation ,DNA - Abstract
DNA can adopt a variety of alternative secondary (i.e., non-B DNA) conformations that play important roles in cellular metabolism, including genetic instability, disease etiology, and evolution. While we still have much to learn, research in this field has expanded dramatically in the past decade. We have summarized in our previous Methods review (Wang et al., Methods, 2009) some commonly used techniques to determine non-B DNA structural conformations and non-B DNA-induced genetic instability in prokaryotes and eukaryotes. Since that time, we and others have further characterized mechanisms involved in DNA structure-induced mutagenesis and have proposed both replication-dependent and replication-independent models. Thus, in this review, we highlight some current methodologies to identify DNA replication-related and replication-independent mutations occurring at non-B DNA regions to allow for a better understanding of the mechanisms underlying DNA structure-induced genetic instability. We also describe a new web-based search engine to identify potential intramolecular triplex (H-DNA) and left-handed Z-DNA-forming motifs in entire genomes or at selected sequences of interest.
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- 2013
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18. DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
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Yi Zhong, Yoko Takata, Sally Gaddis, Martín Carlos Abba, Jaeho Lee, Yue Lu, C. Marcelo Aldaz, Melissa S. Simper, Jianjun Shen, and Hyunsuk Kil
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0301 basic medicine ,PTEN ,Time Factors ,DNA Mutational Analysis ,DMBA ,purl.org/becyt/ford/1 [https] ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,biology ,Pten ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Oncology ,Mice, Inbred DBA ,RANKL ,030220 oncology & carcinogenesis ,Female ,Pik3ca ,CIENCIAS NATURALES Y EXACTAS ,Research Paper ,medicine.medical_specialty ,Class I Phosphatidylinositol 3-Kinases ,9,10-Dimethyl-1,2-benzanthracene ,Otras Ciencias Biológicas ,Medroxyprogesterone Acetate ,Ciencias Biológicas ,03 medical and health sciences ,Internal medicine ,Exome Sequencing ,medicine ,Animals ,HRAS ,purl.org/becyt/ford/1.6 [https] ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Carcinogen ,Sequence Analysis, RNA ,business.industry ,Gene Expression Profiling ,RANK Ligand ,PTEN Phosphohydrolase ,Mammary Neoplasms, Experimental ,Cancer ,PIK3CA ,medicine.disease ,Mice, Inbred C57BL ,Mammary tumors ,MPA ,030104 developmental biology ,Endocrinology ,Mutation ,Ciencias Médicas ,MAMMARY TUMORS ,biology.protein ,Cancer research ,Transcriptome ,business ,Proto-Oncogene Proteins c-akt - Abstract
Controversy always existed on the utility of chemically induced mouse mammary carcinogenesis models as valid equivalents for the study of human breast cancer. Here, we performed whole exome and RNA sequencing on long latency mammary tumors (218 ± 27 days) induced by the carcinogen 7,12-Dimethylbenzathracene (DMBA) and short latency tumors (65 ± 11 days) induced by the progestin Medroxyprogesterone Acetate (MPA) plus DMBA in CD2F1 mice. Long latency tumors displayed a high frequency of Pi3kca and/or Pten mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the Pik3ca H1047L/R hotspot mutation, as frequently found in human breast cancer. These tumors were luminallike and mostly ER/PR+, as in humans. Transcriptome profiling indicated a significant activation of the PI3K-Akt pathway (p=3.82e-6). On the other hand MPA+DMBA induced short latency tumors displayed mutations in cancer drivers not commonly found mutated in human breast cancer (e.g. Hras and Apc). These tumors were mostly basal-like and MPA exposure led to Rankl overexpression (60 fold induction) and immunosuppressive gene expression signatures. In summary, long latency DMBA induced mouse mammary tumors reproduce the molecular profile of human luminal breast carcinomas representing an excellent preclinical model for the testing of PIK3CA/Akt/mTOR pathway inhibitory therapies and a good platform for the developing of additional preclinical tools such as syngeneic transplants in immunocompetent hosts., Facultad de Ciencias Médicas, Centro de Investigaciones Inmunológicas Básicas y Aplicadas
- Published
- 2016
19. Identification of Modulated Genes by Three Classes of Chemopreventive Agents at Preneoplastic Stages in a p53-Null Mouse Mammary Tumor Model
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Jamal Hill, Carla C. Levy, Daniel Medina, Frances S. Kittrell, Reid P. Bissonnette, C. Marcelo Aldaz, Powel H. Brown, Sally Gaddis, Martín Carlos Abba, and Yuhui Hu
- Subjects
Cancer Research ,Tetrahydronaphthalenes ,EGR1 ,Biology ,Article ,Malignant transformation ,Transcriptome ,Mice ,Mammary Glands, Animal ,Gene expression ,Biomarkers, Tumor ,medicine ,Animals ,Anticarcinogenic Agents ,Cyclooxygenase Inhibitors ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Bexarotene ,Mice, Inbred BALB C ,Sulfonamides ,Mammary tumor ,Gene Expression Profiling ,Mammary Neoplasms, Experimental ,Tumor Protein, Translationally-Controlled 1 ,Gefitinib ,FOSL2 ,Molecular biology ,ErbB Receptors ,Gene expression profiling ,Disease Models, Animal ,Oncology ,Celecoxib ,Quinazolines ,Cancer research ,Pyrazoles ,Female ,Tumor Suppressor Protein p53 ,Precancerous Conditions ,medicine.drug - Abstract
Genetically engineered mouse cancer models are among the most useful tools for testing the in vivo effectiveness of the various chemopreventive approaches. The p53-null mouse model of mammary carcinogenesis was previously characterized by us at the cellular, molecular, and pathologic levels. In a companion article, Medina et al. analyzed the efficacy of bexarotene, gefitinib, and celecoxib as chemopreventive agents in the same model. Here we report the global gene expression effects on mammary epithelium of such compounds, analyzing the data in light of their effectiveness as chemopreventive agents. SAGE was used to profile the transcriptome of p53-null mammary epithelium obtained from mice treated with each compound versus controls. This information was also compared with SAGE data from p53-null mouse mammary tumors. Gene expression changes induced by the chemopreventive treatments revealed a common core of 87 affected genes across treatments (P < 0.05). The effective compounds, bexarotene and gefitinib, may exert their chemopreventive activity, at least in part, by affecting a set of 34 genes related to specific cellular pathways. The gene expression signature revealed various genes previously described to be associated with breast cancer, such as the activator protein-1 complex member Fos-like antigen 2 (Fosl2), early growth response 1 (Egr1), gelsolin (Gsn), and tumor protein translationally controlled 1 (Tpt1), among others. The concerted modulation of many of these transcripts before malignant transformation seems to be conducive to predominantly decrease cell proliferation. This study has revealed candidate key pathways that can be experimentally tested in the same model system and may constitute novel targets for future translational research.
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- 2009
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20. Breast Cancer Molecular Signatures as Determined by SAGE: Correlation with Lymph Node Status
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Steve Horvath, Yuhui Hu, Tao Shi, Kathleen A. Hawkins, C. Marcelo Aldaz, Martín Carlos Abba, Hongxia Sun, Sally Gaddis, Aysegul Sahin, Jeffrey A. Drake, and Maria I. Nunez
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Cancer Research ,Databases, Factual ,Transcription, Genetic ,Breast Neoplasms ,Biology ,Article ,Breast cancer ,Gene expression ,medicine ,Humans ,Serial analysis of gene expression ,Molecular Biology ,Lymph node ,DNA Primers ,Neoplasm Staging ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Reverse Transcriptase Polymerase Chain Reaction ,medicine.disease ,Fold change ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,CSNK1D ,Lymphatic Metastasis ,Cancer research ,Female ,Lymph Nodes ,DNA microarray - Abstract
Global gene expression measured by DNA microarray platforms have been extensively used to classify breast carcinomas correlating with clinical characteristics, including outcome. We generated a breast cancer Serial Analysis of Gene Expression (SAGE) high-resolution database of ∼2.7 million tags to perform unsupervised statistical analyses to obtain the molecular classification of breast-invasive ductal carcinomas in correlation with clinicopathologic features. Unsupervised statistical analysis by means of a random forest approach identified two main clusters of breast carcinomas, which differed in their lymph node status (P = 0.01); this suggested that lymph node status leads to globally distinct expression profiles. A total of 245 (55 up-modulated and 190 down-modulated) transcripts were differentially expressed between lymph node (+) and lymph node (−) primary breast tumors (fold change, ≥2; P < 0.05). Various lymph node (+) up-modulated transcripts were validated in independent sets of human breast tumors by means of real-time reverse transcription-PCR (RT-PCR). We validated significant overexpression of transcripts for HOXC10 (P = 0.001), TPD52L1 (P = 0.007), ZFP36L1 (P = 0.011), PLINP1 (P = 0.013), DCTN3 (P = 0.025), DEK (P = 0.031), and CSNK1D (P = 0.04) in lymph node (+) breast carcinomas. Moreover, the DCTN3 (P = 0.022) and RHBDD2 (P = 0.002) transcripts were confirmed to be overexpressed in tumors that recurred within 6 years of follow-up by real-time RT-PCR. In addition, meta-analysis was used to compare SAGE data associated with lymph node (+) status with publicly available breast cancer DNA microarray data sets. We have generated evidence indicating that the pattern of gene expression in primary breast cancers at the time of surgical removal could discriminate those tumors with lymph node metastatic involvement using SAGE to identify specific transcripts that behave as predictors of recurrence as well. (Mol Cancer Res 2007;5(9):881–90)
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- 2007
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21. A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
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Sally Gaddis, Jaeho Lee, Yue Lu, Yoko Takata, Matias Butti, Marcos R. Estecio, Ting Gong, Yi Zhong, Aysegul A. Sahin, Ezequiel Lacunza, C. Marcelo Aldaz, Martín Carlos Abba, and Jianjun Shen
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Cancer Research ,Pathology ,RNA, Untranslated ,T-Lymphocytes, Regulatory ,CDH1 ,purl.org/becyt/ford/1 [https] ,CTLA-4 Antigen ,Breast ,RNA, Neoplasm ,skin and connective tissue diseases ,Exome ,HOTAIR ,DNA, Neoplasm ,Bioquímica y Biología Molecular ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Ductal Carcinoma in Situ ,Oncology ,Female ,CIENCIAS NATURALES Y EXACTAS ,medicine.medical_specialty ,DCIS ,Breast Neoplasms ,Biology ,Article ,Ciencias Biológicas ,Gene Expresssion ,Breast cancer ,Carcinoma Ductal ,Lymphocytes, Tumor-Infiltrating ,Breast Cancer ,Carcinoma ,medicine ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,purl.org/becyt/ford/1.6 [https] ,neoplasms ,Gene Expression Profiling ,Cancer ,Ductal carcinoma ,DNA Methylation ,medicine.disease ,Carcinoma, Intraductal, Noninfiltrating ,Tumor progression ,Ciencias Médicas ,Mutation ,Cancer research ,biology.protein ,Transcriptome ,Genes, Neoplasm - Abstract
Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2 + ) displayed signatures characteristic of activated Treg cells (CD4 + /CD25 + /FOXP3 + ) and CTLA4 + /CD86 + complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer., Centro de Investigaciones Inmunológicas Básicas y Aplicadas
- Published
- 2015
22. Quantitative high-throughput measurement of gene expression with sub-zeptomole sensitivity by capillary electrophoresis
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K. Leslie Powell, Howard D. Thames, Nikki Liburd, Lea Spyres, Stacey Arantes, Michael C. MacLeod, Ella Bedford, Earl F. Walborg, Mahmoud Rouabhia, C. Marcelo Aldaz, David L. Mitchell, and Sally Gaddis
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Keratinocytes ,Biophysics ,Gene Expression ,Bronchi ,Respiratory Mucosa ,Biology ,Sensitivity and Specificity ,Biochemistry ,Genome ,Cell Line ,Capillary electrophoresis ,Gene expression ,Humans ,RNA, Messenger ,Mammary Glands, Human ,Molecular Biology ,Gene ,Detection limit ,Messenger RNA ,Electrophoresis, Capillary ,Epithelial Cells ,Cell Biology ,Fibroblasts ,Genes, p53 ,Fluorescence ,Molecular biology ,Orders of magnitude (mass) ,Female - Abstract
Microarray technologies have provided the ability to monitor the expression of whole genomes rapidly. However, concerns persist with regard to quantitation and reproducibility, and the detection limits for individual genes in particular arrays are generally unknown. This article describes a semiautomated PCR-based technology, Q-RAGE, which rapidly provides measurements of mRNA abundance with extremely high sensitivity using fluorescent detection of specific products separated by capillary electrophoresis. A linear relationship between template concentration and fluorescent signal can be demonstrated down to template concentrations in the low aM region, corresponding to approximately 0.04 zmol (24 molecules) per reaction. The technique is shown to be quantitative over five orders of magnitude of template concentration, and average mRNA abundances of approximately 0.01 molecule per cell can be detected. A single predefined set of 320 primers provides 90–95% coverage of all eukaryotic genomes. Analysis of a set of 19 p53-regulated genes in untreated cultures of normal human epithelial cells, derived from three different tissues, revealed a 600-fold range of apparent constitutive expression levels. For most of the genes assayed, good correlations were observed among the expression levels in normal mammary, bronchial, and epidermal epithelial cells.
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- 2005
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23. From Mice to Humans
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Daniel Medina, C. Marcelo Aldaz, Martín Carlos Abba, Hongxia Sun, Yuhui Hu, Sally Gaddis, Frances S. Kittrell, Aysegul Sahin, Keith A. Baggerly, Jeffrey A. Drake, and Li Deng
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Regulation of gene expression ,Genetics ,Cancer Research ,Cancer Model ,Cancer ,Biology ,medicine.disease ,medicine.disease_cause ,Gene expression profiling ,Breast cancer ,Oncology ,medicine ,Cancer research ,Gene family ,Serial analysis of gene expression ,Carcinogenesis - Abstract
Genetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (>300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (>2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBα), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets.This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
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- 2004
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24. Serial analysis of gene expression in normal p53 null mammary epithelium
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Sally Gaddis, Yuhui Hu, Frances S. Kittrell, C. Marcelo Aldaz, Daniel Medina, and Rachael L. Daniel
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Cancer Research ,Biology ,medicine.disease_cause ,Transcriptome ,Mice ,Mammary Glands, Animal ,Gene expression ,Genetics ,medicine ,Animals ,Humans ,Serial analysis of gene expression ,Molecular Biology ,Expressed Sequence Tags ,Mice, Inbred BALB C ,Gene Expression Profiling ,Epithelial Cells ,Genes, p53 ,Null allele ,Epithelium ,Gene expression profiling ,medicine.anatomical_structure ,Gene Expression Regulation ,Mammary Epithelium ,Cytochrome P-450 CYP1B1 ,Cancer research ,Female ,Aryl Hydrocarbon Hydroxylases ,Carcinogenesis - Abstract
Much evidence has accumulated implicating the p53 gene as of importance in breast carcinogenesis. However, much still remains to be uncovered on the specific downstream pathways influenced by this important activator/repressor of transcription. This study investigated the effects of a p53 null genotype on the transcriptome of 'normal' mouse mammary epithelium using a unique in vivo model of preneoplastic transformation. We used SAGE for the comparative analysis of p53 wild type (wt) and null mammary epithelium unexposed and exposed to hormonal stimulation. Analysis of the hormone exposed samples provided a comprehensive view of the dramatic changes in gene expression as consequence of the functional differentiation of the mammary epithelium in an in vivo system. We detected the dysregulation in p53(null) epithelium of
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- 2002
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25. Gene expression signature of estrogen receptor α status in breast cancer
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Sally Gaddis, Yuhui Hu, Martín Carlos Abba, C. Marcelo Aldaz, Aysegul A. Sahin, Keith A. Baggerly, Hongxia Sun, and Jeffrey A. Drake
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Genetic Markers ,lcsh:QH426-470 ,lcsh:Biotechnology ,Estrogen receptor ,Breast Neoplasms ,Biology ,Response Elements ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,lcsh:TP248.13-248.65 ,Databases, Genetic ,Genetics ,medicine ,Biomarkers, Tumor ,Humans ,Serial analysis of gene expression ,Estrogen receptor beta ,030304 developmental biology ,Gene Library ,0303 health sciences ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Estrogen Receptor alpha ,Cancer ,Computational Biology ,Estrogens ,medicine.disease ,Molecular biology ,Immunohistochemistry ,3. Good health ,Up-Regulation ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,lcsh:Genetics ,Phenotype ,030220 oncology & carcinogenesis ,Steroid hormone receptor activity ,Estrogen receptor alpha ,Biotechnology ,Research Article - Abstract
Background Estrogens are known to regulate the proliferation of breast cancer cells and to modify their phenotypic properties. Identification of estrogen-regulated genes in human breast tumors is an essential step toward understanding the molecular mechanisms of estrogen action in cancer. To this end we generated and compared the Serial Analysis of Gene Expression (SAGE) profiles of 26 human breast carcinomas based on their estrogen receptor α (ER) status. Thus, producing a breast cancer SAGE database of almost 2.5 million tags, representing over 50,000 transcripts. Results We identified 520 transcripts differentially expressed between ERα-positive (+) and ERα-negative (-) primary breast tumors (Fold change ≥ 2; p < 0.05). Furthermore, we identified 220 high-affinity Estrogen Responsive Elements (EREs) distributed on the promoter regions of 163 out of the 473 up-modulated genes in ERα (+) breast tumors. In brief, we observed predominantly up-regulation of cell growth related genes, DNA binding and transcription factor activity related genes based on Gene Ontology (GO) biological functional annotation. GO terms over-representation analysis showed a statistically significant enrichment of various transcript families including: metal ion binding related transcripts (p = 0.011), calcium ion binding related transcripts (p = 0.033) and steroid hormone receptor activity related transcripts (p = 0.031). SAGE data associated with ERα status was compared with reported information from breast cancer DNA microarrays studies. A significant proportion of ERα associated gene expression changes was validated by this cross-platform comparison. However, our SAGE study also identified novel sets of genes as highly expressed in ERα (+) invasive breast tumors not previously reported. These observations were further validated in an independent set of human breast tumors by means of real time RT-PCR. Conclusion The integration of the breast cancer comparative transcriptome analysis based on ERα status coupled to the genome-wide identification of high-affinity EREs and GO over-representation analysis, provide useful information for validation and discovery of signaling networks related to estrogen response in this malignancy.
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- 2005
26. SAGE profiling of UV-induced mouse skin squamous cell carcinomas, comparison with acute UV irradiation effects
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Thomas R. Berton, David G. Johnson, Amy Pavone, Hyunsuk Kil, Kathleen A. Hawkins, Russell D. Klein, Susan M. Fischer, Elisabeth McCauley, Sally Gaddis, Ronald A. Lubet, Joyce E. Rundhaug, and C. Marcelo Aldaz
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Cancer Research ,Ultraviolet Rays ,Gene Expression ,Biology ,medicine.disease_cause ,Mice ,Gene expression ,medicine ,Animals ,Northern blot ,Serial analysis of gene expression ,Molecular Biology ,Skin ,integumentary system ,Gene Expression Profiling ,medicine.disease ,Blotting, Northern ,Gene expression profiling ,Blot ,stomatognathic diseases ,Immunology ,Cancer research ,Carcinoma, Squamous Cell ,CCL27 ,Female ,Skin cancer ,Carcinogenesis - Abstract
Ultraviolet (UV) irradiation is the primary environmental insult responsible for the development of most common skin cancers. To better understand the multiple molecular events that contribute to the development of UV-induced skin cancer, in a first study, serial analysis of gene expression (SAGE) was used to compare the global gene expression profiles of normal SKH-1 mice epidermis with that of UV-induced squamous cell carcinomas (SCCs) from SKH-1 mice. More than 200 genes were found to be differentially expressed in SCCs compared to normal skin (P < 0.0005 level of significance). As expected, genes related to epidermal proliferation and differentiation were deregulated in SCCs relative to normal skin. However, various novel genes, not previously associated with skin carcinogenesis, were also identified as deregulated in SCCs. Northern blot analyses on various selected genes validated the SAGE findings: caspase-14 (reduced 8.5-fold in SCCs); cathepsins D and S (reduced 3-fold and increased 11.3-fold, respectively, in SCCs); decorin, glutathione S-transferase omega-1, hypoxia-inducible factor 1 alpha, insulin-like growth factor binding protein-7, and matrix metalloproteinase-13 (increased 18-, 12-, 12-, 18.3-, and 11-folds, respectively, in SCCs). Chemokine (C-C motif), ligand 27 (CCL27), which was found downregulated 12.7-fold in SCCs by SAGE, was also observed to be strongly downregulated 6-24 h after a single and multiple UV treatments. In a second independent study we compared the expression profile of UV-irradiated versus sham-treated SKH-1 epidermis. Interestingly, numerous genes determined to be deregulated 8 h after a single UV dose were also deregulated in SCCs. For instance, genes whose expression was upregulated both after acute UV-treated skin and SCCs included keratins 6 and 16, small proline-rich proteins, and S100 calcium binding protein A9. Studies like those described here do not only provide insights into genes and pathways involved in skin carcinogenesis but also allow us to identify early UV irradiation deregulated surrogate biomarkers of potential use in chemoprevention studies.
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- 2004
27. From mice to humans: identification of commonly deregulated genes in mammary cancer via comparative SAGE studies
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Yuhui, Hu, Hongxia, Sun, Jeffrey, Drake, Frances, Kittrell, Martin C, Abba, Li, Deng, Sally, Gaddis, Aysegul, Sahin, Keith, Baggerly, Daniel, Medina, and C Marcelo, Aldaz
- Subjects
Interleukin-6 ,Chemokine CXCL1 ,Gene Expression Profiling ,NF-kappa B ,Mammary Neoplasms, Experimental ,Proteins ,Apoptosis ,Breast Neoplasms ,Leukemia Inhibitory Factor ,Article ,Gene Expression Regulation, Neoplastic ,Mice ,Animals ,Cytokines ,Humans ,Intercellular Signaling Peptides and Proteins ,Female ,Chemokines, CXC ,Cell Division ,Chemokine CCL2 - Abstract
Genetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBalpha), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets. This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
- Published
- 2004
28. Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression
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Kathleen A. Hawkins, Martín Carlos Abba, Aysegul A. Sahin, Sally Gaddis, Jeffery A. Drake, C. Marcelo Aldaz, Hongxia Sun, Keith A. Baggerly, Yuhui Hu, and Cinitia Notcovich
- Subjects
Pathology ,medicine.medical_specialty ,Gene Expression ,Apoptosis ,Breast Neoplasms ,Biology ,Transcriptome ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,Gene expression ,medicine ,Humans ,Gene family ,Neoplasm Invasiveness ,Serial analysis of gene expression ,Neoplasm Metastasis ,Gene Library ,030304 developmental biology ,Medicine(all) ,0303 health sciences ,Tumor Necrosis Factor-alpha ,Gene Expression Profiling ,Carcinoma, Ductal, Breast ,Cell Cycle ,NF-kappa B ,Cancer ,Ductal carcinoma ,medicine.disease ,Extracellular Matrix ,3. Good health ,Gene expression profiling ,Carcinoma, Intraductal, Noninfiltrating ,030220 oncology & carcinogenesis ,Cancer research ,serial analysis of gene expression ,Cell Division ,Research Article - Abstract
Introduction Genomic and transcriptomic alterations affecting key cellular processes such us cell proliferation, differentiation and genomic stability are considered crucial for the development and progression of cancer. Most invasive breast carcinomas are known to derive from precursor in situ lesions. It is proposed that major global expression abnormalities occur in the transition from normal to premalignant stages and further progression to invasive stages. Serial analysis of gene expression (SAGE) was employed to generate a comprehensive global gene expression profile of the major changes occurring during breast cancer malignant evolution. Methods In the present study we combined various normal and tumor SAGE libraries available in the public domain with sets of breast cancer SAGE libraries recently generated and sequenced in our laboratory. A recently developed modified t test was used to detect the genes differentially expressed. Results We accumulated a total of approximately 1.7 million breast tissue-specific SAGE tags and monitored the behavior of more than 25,157 genes during early breast carcinogenesis. We detected 52 transcripts commonly deregulated across the board when comparing normal tissue with ductal carcinoma in situ, and 149 transcripts when comparing ductal carcinoma in situ with invasive ductal carcinoma (P < 0.01). Conclusion A major novelty of our study was the use of a statistical method that correctly accounts for the intra-SAGE and inter-SAGE library sources of variation. The most useful result of applying this modified t statistics beta binomial test is the identification of genes and gene families commonly deregulated across samples within each specific stage in the transition from normal to preinvasive and invasive stages of breast cancer development. Most of the gene expression abnormalities detected at the in situ stage were related to specific genes in charge of regulating the proper homeostasis between cell death and cell proliferation. The comparison of in situ lesions with fully invasive lesions, a much more heterogeneous group, clearly identified as the most importantly deregulated group of transcripts those encoding for various families of proteins in charge of extracellular matrix remodeling, invasion and cell motility functions.
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- 2004
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29. Abstract B22: Molecular oncogenesis of NANOG in castration-resistant prostate cancer
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Collene R. Jeter, Yue Lu, Sally Gaddis, Shoudan Liang, Dean G. Tang, and Bigang Liu
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Homeobox protein NANOG ,Cancer Research ,Biology ,Bioinformatics ,medicine.disease ,medicine.disease_cause ,Chromatin remodeling ,Prostate cancer ,Oncology ,embryonic structures ,LNCaP ,Cancer cell ,medicine ,Cancer research ,Epigenetics ,Stem cell ,Carcinogenesis - Abstract
Regardless of the cell-of-origin, self-renewing tumor cells may be a driving force in cancer progression to lethal disease. An important outstanding question in the field of oncology is by what molecular mechanisms do tumor cells acquire stem cell (SC) biological properties? The embryonic stem cell pluripotency molecule NANOG appears to be among the important SC-related self-renewal genes underlying molecular oncogenesis. We have previously reported that NANOG attenuation inhibited prostate cancer cell clonogenic growth and in vivo tumorigenicity. Subsequently, we have found that NANOG overexpression in LNCaP prostate cancer cells promoted clonogenicity and tumor development particularly in androgen-deprived conditions. Furthermore, NANOG knockdown in relatively undifferentiated PSA- prostate cancer cells significantly reduced tumor regeneration in castrated hosts implicating NANOG in the emergence of castration-resistant prostate cancer (CRPC). To understand the molecular underpinnings of NANOG-mediated CRPC, we have performed ChIP-Seq analysis of NANOG occupancy in LNCaP cells overexpressing NANOGP8 or NANOG1. These non-biased and global studies have revealed downstream genes and signaling pathways that may potentially be regulated by NANOG in cancer cells and shed light on the NANOG castration-resistance phenotype. ∼60% of the promoter occupied sites are shared between NANOGP8 and NANOG1, representing 806 genes. Among these are many developmental-associated genes, chromatin remodeling and epigenetic regulators and molecules implicated in prostate cancer. In addition, motif analysis of NANOG occupied regions has revealed a novel candidate NANOG-interacting protein in prostate cancer cells. Integration of ChIP-Seq data with RNA-Seq is currently underway and integrative analysis is anticipated to further discriminate the direct and indirect molecular architecture responding to NANOG expression in prostate cancer. Citation Format: Collene R. Jeter, Yue Lu, Bigang Liu, Sally Gaddis, Shoudan Liang, Dean G. Tang. Molecular oncogenesis of NANOG in castration-resistant prostate cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B22.
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- 2012
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30. Correction: Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression
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Aysegul Sahin, Kathleen A. Hawkins, Cinitia Notcovich, Martín Carlos Abba, C. Marcelo Aldaz, Sally Gaddis, Jeffery A. Drake, Yuhui Hu, Keith A. Baggerly, and Hongxia Sun
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Transcriptome ,Oncology ,medicine.medical_specialty ,Breast cancer ,business.industry ,Internal medicine ,Medicine ,Cancer ,Correction ,Serial analysis of gene expression ,business ,medicine.disease ,Human breast - Published
- 2004
31. SAGE profiling of UV-induced mouse skin squamous cell carcinomas, comparison with acute UV irradiation effectsBoth authors (S.M.F. and C.M.A.) contributed equally to this study.
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Joyce E. Rundhaug, Kathleen A. Hawkins, Amy Pavone, Sally Gaddis, Hyunsuk Kil, Russell D. Klein, Thomas R. Berton, Elisabeth McCauley, David G. Johnson, Ronald A. Lubet, Susan M. Fischer, and C. Marcelo Aldaz
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- 2005
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32. Transcriptomic signature of Bexarotene (Rexinoid LGD1069) on mammary gland from three transgenic mouse mammary cancer models
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C. Marcelo Aldaz, Frances S. Kittrell, Yun Zhang, Reid P. Bissonnette, Jamal Hill, Sally Gaddis, Martín Carlos Abba, Daniel Medina, Yuhui Hu, Carla C. Levy, and Powel H. Brown
- Subjects
Genetically modified mouse ,lcsh:Internal medicine ,lcsh:QH426-470 ,medicine.drug_class ,Mammary gland ,Retinoid X receptor ,Biology ,Bioinformatics ,Transcriptome ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,medicine ,Genetics ,Genetics(clinical) ,Retinoid ,lcsh:RC31-1245 ,Genetics (clinical) ,030304 developmental biology ,Bexarotene ,0303 health sciences ,Cell growth ,Cancer ,medicine.disease ,3. Good health ,lcsh:Genetics ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Ciencias Médicas ,Cancer research ,Biomarkers ,Research Article ,medicine.drug - Abstract
Background: The rexinoid bexarotene (LGD1069, Targretin) is a highly selective retinoid × receptor (RXR) agonist that inhibits the growth of pre-malignant and malignant breast cells. Bexarotene was shown to suppress the development of breast cancer in transgenic mice models without side effects. The chemopreventive effects of bexarotene are due to transcriptional modulation of cell proliferation, differentiation and apoptosis. Our goal in the present study was to obtain a profile of the genes modulated by bexarotene on mammary gland from three transgenic mouse mammary cancer models in an effort to elucidate its molecular mechanism of action and for the identification of biomarkers of effectiveness. Methods: Serial analysis of gene expression (SAGE) was employed to profile the transcriptome of p53-null, MMTV-ErbB2, and C3(1)-SV40 mammary cells obtained from mice treated with bexarotene and their corresponding controls. Results: This resulted in a dataset of approximately 360,000 transcript tags representing over 20,000 mRNAs from a total of 6 different SAGE libraries. Analysis of gene expression changes induced by bexarotene in mammary gland revealed that 89 genes were dysregulated among the three transgenic mouse mammary models. From these, 9 genes were common to the three models studied. Conclusion: Analysis of the indicated core of transcripts and protein-protein interactions of this commonly modulated genes indicate two functional modules significantly affected by rexinoid bexarotene related to protein biosynthesis and bioenergetics signatures, in addition to the targeting of cancer-causing genes related with cell proliferation, differentiation and apoptosis., Centro de Investigaciones Inmunológicas Básicas y Aplicadas
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33. Response of human mammary epithelial cells to DNA damage induced by BPDE: Involvement of novel regulatory pathways
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Michael C. MacLeod, C. Marcelo Aldaz, Harsha Mistry, Jing Gu, Sally Gaddis, Aijin Wang, Kimberly Judson-Kremer, Padmaja Simhambhatla, and K. Leslie Powell
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Cyclin-Dependent Kinase Inhibitor p21 ,Cancer Research ,Gadd45 ,DNA damage ,Gene Expression Profiling ,7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide ,Cell Cycle ,Epithelial Cells ,General Medicine ,DNA ,Cell cycle ,Biology ,Molecular biology ,Gene expression profiling ,Transactivation ,DNA Adducts ,Cyclins ,Gene expression ,Carcinogens ,Humans ,Breast ,Tumor Suppressor Protein p53 ,Gene ,Nucleotide excision repair ,DNA Damage - Abstract
The responses of a line of normal human mammary epithelial cells, HME87, to treatment with the ultimate carcinogen benzo[a]pyrene diol epoxide (BPDE) were analyzed using a directed gene expression analysis technique, RAGE. Under conditions where cell number was decreased by 50% 24 or 48 h post-treatment, flow cytometry demonstrated no establishment of a G(1)/S arrest nor induction of apoptosis; cells continued to enter S phase from G(1) for at least 24 h but were blocked at G(2)/M. Using the RAGE technique, changes in gene expression were assayed for over 1000 genes, and multiple time-point data were collected for approximately 90 genes. In accord with the cell cycle studies, expression of the p21-WAF1 gene, the major mediator of p53-dependent G(1)/S arrest, did not increase until 24 h post-treatment. The expression of other target genes for transactivation by p53 was increased at early time points, including GADD45, an effector of the G(2)/M checkpoint, and WIP1. Analyses of proteins in treated cells indicated that p53 was phosphorylated at Ser15 but not at Ser20 within 30 min of treatment, and this correlated with an increase in the total amount of p53 protein. Significant expression changes were noted in a number of transcription factor genes, including ATF3 and E2A, genes that have not been previously connected to a response to DNA damage involving bulky chemical adducts. In addition, expression of the XPC gene was induced by BPDE treatment; the XPC product is thought to be involved in recognition of DNA damage by the nucleotide excision repair system.
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