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While tremendous improvement has been made for the treatment of breast cancers, the treatment of triple negative breast cancer (TNBC) still remains a challenge due to its aggressive characteristics and limited treatment options. Most of the studies on TNBC were conducted in Western population and TNBC is reported to be more frequent in the African women. This review encapsulates the studies conducted on TNBC patients in Asian population and elucidates the similarities and differences between these two regions. The current treatment of TNBC includes surgery, radiotherapy and chemotherapy. In addition to the current chemotherapies, which mainly include cytotoxic agents, such as taxanes and anthracyclines, many clinical trials are investigating the potential use of other chemotherapy drugs, targeted therapeutics and combinational therapies to treat TNBC. Moreover, this review also integrates the studies involving novel markers, which will help us to dissect the pathologic process of TNBC and in turn facilitate the development of better treatment strategies to combat TNBC. [ABSTRACT FROM AUTHOR]

Abstract: A growing body of recent literature indicates that in addition to an essential role in growth and development, growth hormone may also play a more sinister role in oncogenic transformation and neoplastic progression. Here we review the accumulating evidence implicating growth hormone in the development and progression of cancer and describe what is known of the mechanisms utilised by this hormone in neoplastic transformation. [Copyright &y& Elsevier]

GLP-1 receptor agonists are clinically utilized for type 2 diabetes and obesity. In vitro and in vivo preclinical studies were performed to assess the druggability of a novel small molecule GLP-1 receptor biased agonist SAL0112. The HTRF assay, FLIPR assay, TR-FRET assay, and PathHunter assay were utilized for in vitro studies. Liver transporter tests were conducted using the HEK293-OATP1B1 and HEK293-OATP1B3 cell lines. In vitro stability assessments of various species and in vivo PK studies in rodents were performed. A model of type 2 diabetes and obesity induced by a high-energy diet in transgenic C57BL/6 mice expressing the human GLP-1 receptor gene was conducted. SAL0112 demonstrated high potency and selectivity in activating the Gαs pathway of the GLP-1 receptor, with no observed desensitization. SAL0112 demonstrated greater stability in human and rat liver microsomes compared to Danuglipron. In vivo PK studies revealed higher absorption of SAL0112 in rats. SAL0112 displayed a significantly lower potential for DDI on liver transporters compared to Danuglipron. SAL0112 led to significant reductions in body weight (P <0.001), blood glucose levels in OGTT (P <0.001), HbA 1c (P <0.05) and improved insulin resistance (P <0.01). Notably, it increased peripheral adipocyte density and resolved hepatic steatosis. The efficacy of SAL0112 was found to be comparable to that of Danuglipron and Liraglutide. SAL0112 demonstrated potent and selective GLP-1 receptor biased agonism, effectively alleviating signs of type 2 diabetes in a mouse model. These promising findings pave the way for the advancement of SAL0112 into clinical trials. [Display omitted] • This research is the first to report the desensitization effect of small molecule GLP-1 receptor biased agonists. • SAL0112 is a novel GLP-1 receptor biased agonist that offers a better pharmacokinetic profile than Danuglipron. • SAL0112 significantly alleviated the early symptoms of type 2 diabetes. [ABSTRACT FROM AUTHOR]

We demonstrate here that growth hormone (GH) stimulates the activation of Rap1 and Rap2 in NIH-3T3 cells. Full activation of Rap1 and Rap2 by GH necessitated the combined activity of both JAK2 and c-Src kinases, although c-Src was predominantly required. GH-stimulated Rap1 and Rap2 activity was also demonstrated to be CrkII-C3G-dependent. GH stimulated the tyrosine phosphorylation of C3G, which again required the combined activity of JAK2 and c-Src. C3G tyrosine residue 504 was required for GH-stimulated Rap activation. Activated Rap1 inhibited GH-stimulated activation of Ra1A and subsequent GH-stimulated p44/42 MAP kinase activity and Elk-1-mediated transcription. In addition, we demonstrated that C3G-Rap1 mediated CrkII enhancement of GH-stimulated JNK/SAPK activity. We have therefore identified a linear JAK2-independent pathway switching GH-stimulated p44/42 MAP kinase and JNK/SAPK activities. [ABSTRACT FROM AUTHOR]

Nearly 70% of ovarian cancer (OC) patients experience recurrence within the first 2 years after initial treatment. Emerging evidence indicates that long non-coding RNAs (lncRNAs) play a pivotal role in the pathogenesis of OC progression, resistance to therapy and recurrent OC (ROC). Transcriptome profiling studies have reported differential expression patterns of lncRNAs in OC which are related to increased cell invasion, metastasis and drug resistance. In this review, we highlighted the roles of lncRNAs in OC progression and outlined the potential molecular mechanisms by which lncRNAs impact on ROC. Recent advances using lncRNAs as potential biomarkers for screening, detection, prediction, response to therapy and as therapeutic targets are discussed. [ABSTRACT FROM AUTHOR]

Precision medicine promises to better classify patients by individual clinical and biological biomarkers, which may provide an accurate assessment of disease risk, diagnosis, prognosis and treatment response. Cancer frequently displays substantial inter-tumor and intra-tumor heterogeneity and hence oncology is well suited for application of precision approaches. Recent studies have demonstrated that dysregulated lncRNAs play pivotal roles in tumor heterogeneity. In this review, attention is focused on the potential applications of lncRNAs as biomarker candidates for cancer risk evaluation, detection, surveillance and prognosis. LncRNAs are often stable in clinical samples and easily detected. The functional implications and therapeutic potential of targeting lncRNAs in human cancer are further discussed. Finally, existing deficiencies and future perspectives in translating fundamental lncRNA knowledge into clinical practice are highlighted. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5- a ]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2′-ethoxy-4′-fluoro-[1,1′-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole (EFT) as lead cytotoxic agent against MCF7 cell lines with an IC 50 value of 1.69 µM. Further evaluation revealed that EFT induces cytotoxicity on Ishikawa, MDA-MB-231 and BT474 cells with IC 50 values of 1.97, 4.81 and 4.08 µM respectively. However, EFT did not induce cytotoxicity in normal lung epithelial (BEAS-2B) cells. Previous reports suggested that 1,2,3-triazoles are the inhibitors of VEGFR1 and therefore, we evaluated the effect of EFT on the expression of VEGFR1. The results demonstrated that EFT downregulates the expression of VEGFR1 in MCF7 cells. In summary, we identified a potent cytotoxic agent that imparts its antiproliferative activity by targeting VEGFR1 in breast cancer cells. The novel compound could serve as a lead structure in developing VEGFR1 inhibitors. [ABSTRACT FROM AUTHOR]

Gastric cancer remains a malignancy with poor survival outcome. We herein report that GSE1, a proline-rich protein, possesses a role in the progression of human gastric cancer. The expression of GSE1 was observed to be much higher in human gastric cancer tissues compared with normal gastric tissues, and GSE1 expression correlated positively with lymph node metastasis, histological grade, depth of invasion, and clinical stage in gastric cancer patients. Moreover, GSE1 expression was also associated with decreased post-operative relapse-free survival and overall survival in the cohort. The forced expression of GSE1 in gastric cancer cell lines resulted in increased cell proliferation, increased colony formation, enhanced cell migration, and invasion. Furthermore, forced expression of GSE1 also increased tumor size and enhanced lung metastasis in xenograft models. The depletion of endogenous GSE1 with shRNAs decreased the oncogenicity and invasiveness of gastric cancer cells both in vitro and in vivo. In addition, GSE1 was determined to be a direct target of miR-200b and miR-200c. Furthermore, GSE1 positively regulated the downstream gene SLC7A5 (also known as LAT-1), which was scanned and verified from mRNA sequencing. GSE1 therefore possesses an oncogenic role in human gastric cancer, and targeted therapeutic approaches to inhibit GSE1 function in gastric cancer warrant further consideration. [ABSTRACT FROM AUTHOR]

The glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs)comprising of GDNF, neurturin, artemin, and persephin plays an important role in the development and maintenance of the central and peripheral nervous system, renal morphogenesis, and spermatogenesis. Here we review our current understanding of GFL biology, and supported by recent progress in the area, we examine their emerging role in endocrine-related and other non-hormone-dependent solid neoplasms. The ability of GFLs to elicit actions that resemble those perturbed in an oncogenic phenotype, alongside mounting evidence of GFL involvement in tumor progression, presents novel opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the posttranscriptional level by miR26a/b and the RNA-binding protein human antigen R (HuR), both of which associate with the 3′-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMRER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3′-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3′-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells. [ABSTRACT FROM AUTHOR]

The growth hormone (GH) and insulin-like growth factor-1 (IGF1) axis is the key regulator of longitudinal growth, promoting postnatal bone and muscle growth. The available data suggest that GH expression by tumour cells is associated with the aetiology and progression of various cancers such as endometrial, breast, liver, prostate, and colon cancer. Accordingly there has been increased interest in targeting GH-mediated signal transduction in a therapeutic setting. Because GH has endocrine, autocrine, and paracrine actions, therapeutic strategies will need to take into account systemic and local functions. Activation of related hormone receptors and crosstalk with other signalling pathways are also key considerations. [ABSTRACT FROM AUTHOR]

The oncogenic effects of autocrine human growth hormone (hGH) have been intensively investigated in estrogen receptor-positive mammary carcinoma (ER + MC) cells. We demonstrated herein that autocrine hGH promoted cancer stem cell (CSC)-like properties of estrogen receptor-negative mammary carcinoma (ER-MC) cells in vitro. In xenograft studies, autocrine hGH increased the tumor initiating capacity of ER-MC cells. We also observed that autocrine hGH promoted migration and invasion of ER-MC cells in vitro , and metastasis in vivo . Thus, inhibition of hGH is a potential therapeutic strategy to prevent tumor initiation and metastasis of ER-MC. [ABSTRACT FROM AUTHOR]

Human growth hormone (hGH) plays critical roles in pubertal mammary gland growth, development, and sexual maturation. Accumulated studies have reported that autocrine/paracrine hGH is an orthotopically expressed oncoprotein that promotes normal mammary epithelial cell oncogenic transformation. Autocrine/paracrine hGH has also been reported to promote mammary epithelial cell epithelial-mesenchymal transition (EMT) and invasion. However, the underlying mechanism remains largely obscure. MicroRNAs (miRNAs) are reported to be involved in regulation of multiple cellular functions of cancer. To determine whether autocrine/paracrine hGH promotes EMT and invasion through modulation of miRNA expression, we performed microarray profiling using MCF-7 cells stably expressing wild type or a translation-deficient hGH gene and identified miR-96-182-183 as an autocrine/paracrine hGH-regulated miRNA cluster. Forced expression of miR-96-182-183 conferred on epithelioid MCF-7 cells a mesenchymal phenotype and promoted invasive behavior in vitro and dissemination in vivo. Moreover, we observed that miR-96-182-183 promoted EMT and invasion by directly and simultaneously suppressing BRMS1L (breast cancer metastasis suppressor 1-like) gene expression. miR-96 and miR-182 also targeted GHR, providing a potential negative feedback loop in the hGH-GHR signaling pathway. We further demonstrated that autocrine/paracrine hGH stimulated miR-96-182-183 expression and facilitated EMT and invasion via STAT3 and STAT5 signaling. Consistent with elevated expression of autocrine/paracrine hGH in metastatic breast cancer tissue, miR-96-182-183 expression was also remarkably enhanced. Hence, we delineate the roles of the miRNA-96-182-183 cluster and elucidate a novel hGH-GHR-STAT3/STAT5-miR-96-182-183-BRMS1L-ZEB1/E47-EMT/invasion axis, which provides further understanding of the mechanism of autocrine/paracrine hGH-stimulated EMT and invasion in breast cancer. [ABSTRACT FROM AUTHOR]

Trefoil factor 3 (TFF3) is a secreted protein which functions in mucosal repair of the gastrointestinal tract. This is achieved through the combined stimulation of cell migration and prevention of apoptosis and anoikis, thus facilitating repair. Deregulated TFF3 expression at the gene and protein level is implicated in numerous cancers. In prostate cancer TFF3 has previously been reported as a potential biomarker, overexpressed in a subset of primary and metastatic cases. Here we investigated the effect of increased TFF3 expression on prostate cancer cell behaviour. Oncomine analysis demonstrated that TFF3 mRNA expression was upregulated in prostate cancer compared to normal tissue. Forced-expression models were established in the prostate cancer cell lines, DU145 and PC3, by stable transfection of an expression vector containing the TFF3 cDNA. Forced expression of TFF3 significantly increased total cell number and cell viability, cell proliferation and cell survival. In addition, TFF3 enhanced anchorage independent growth, 3-dimensional colony formation, wound healing and cell migration compared to control transfected cell lines. We also observed reduced sensitivity to ionising radiation in stably transfected cell lines. In dose response experiments, forced expression of TFF3 significantly enhanced the regrowth of PC3 cells following ionising radiation compared with control transfected cells. In addition, TFF3 enhanced clonogenic survival of DU145 and PC3 cells. These studies indicate that targeting TFF3 for the treatment of prostate cancer warrants further investigation. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation, and survival, and given its association with many types of cancers, it has recently emerged as a promising target for therapy. In this work, we present the synthesis of N-substituted azaspirane derivatives and their biological evaluation against hepatocellular carcinoma (HCC) cells (IC50 = 7.3 µM), thereby identifying 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5) undecane (CIMO) as a potent inhibitor of the JAK-STAT pathway with selectivity over normal LO2 cells (IC50 >100µM). The lead compound, CIMO, suppresses proliferation of HCC cells and achieves this effect by reducing both constitutive and inducible phosphorylation of JAK1, JAK2, and STAT3. Interestingly, CIMO displayed inhibition of Tyr-705 phosphorylation, which is required for nuclear translocation of STAT3, but it has no effect on Ser-727 phosphorylation. CIMO accumulates cancer cells in the sub-G1 phase and decreases STAT3 in the nucleus and thereby causes down-regulation of genes regulated via STAT3. Suppression of STAT3 phosphorylation by CIMO and knockdown of STAT3 mRNA using siRNA transfection displayed a similar effect on the viability of HCC cells. Furthermore, CIMO significantly decreased the tumor development in an orthotopic HCC mouse model through the modulation of phospho-STAT3, Ki-67, and cleaved caspase-3 in tumor tissues. Thus, CIMO represents a chemically novel and biologically in vitro and in vivo validated compound, which targets the JAKSTAT pathway as a potential cancer treatment. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that Artemin (ARTN) functions as a cancer stem cell (CSC) and metastatic factor in mammary carcinoma. Herein, we report that ARTN mediates acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells. Ligands that increase HER2 activity increased ARTN expression in HER2-positive mammary carcinoma cells, whereas trastuzumab inhibited ARTN expression. Forced expression of ARTN decreased the sensitivity of HER2-positive mammary carcinoma cells to trastuzumab both in vitro and in vivo. Conversely, siRNA-mediated depletion of ARTN enhanced trastuzumab efficacy. Cells with acquired resistance to trastuzumab exhibited increased ARTN expression, the depletion of which restored trastuzumab sensitivity. Trastuzumab resistance produced an increased CSC population concomitant with enhanced mammospheric growth. ARTN mediated the enhancement of the CSC population by increased BCL-2 expression, and the CSC population in trastuzumab-resistant cells was abrogated upon inhibition of BCL-2. Hence, we conclude that ARTN is one mediator of acquired resistance to trastuzumab in HER2-positive mammary carcinoma cells. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that the miR-23a/24-2/27a cluster may possess a causal role in mammary tumorigenesis and function as a novel class of oncogenes. However, the regulatory mechanism of the miR-23a/24-2/27a cluster in mammary carcinoma cell invasion and migration is still largely unknown. We observed that the expression levels of miR-23a, miR-24-2 and miR-27a were significantly higher in breast cancer with lymph node metastasis, compared with that from patients without lymph node metastasis or normal tissue. Forced expression of the miR-23a/24-2/27a cluster promoted mammary carcinoma cell migration, invasion, and hepatic metastasis, through targeting Sprouty2 (SPRY2) and consequent activation of p44/42 MAPK. Epidermal growth factor induced the expression of the transcription factor c-MYC, which promoted the expression of mature miR-23a, miR-24-2, and miR-27a and subsequently decreased expression of SPRY2 and activated p44/42 MAPK to promote mammary carcinoma cell migration and invasion. We therefore suggest a novel link between epidermal growth factor and the miR-23a/24-2/27a cluster via the regulation of c-MYC, providing the potential for the miR-23a/24-2/27a cluster to be used as biomarker in the diagnosis and/or treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Artemin (ARTN) has been reported to promote a TWIST1- dependent epithelial to mesenchymal transition of estrogen receptor negative mammary carcinoma (ER-MC) cells associated with metastasis and poor survival outcome. We therefore examined a potential role of ARTN in the promotion of the cancer stem cell (CSC)-like phenotype in mammary carcinoma cells. Acquired resistance of ER-MC cells to either ionizing radiation (IR) or paclitaxel was accompanied by increased ARTN expression. Small interfering RNA (siRNA)-mediated depletion of ARTN in either IR- or paclitaxel-resistant ER-MC cells restored cell sensitivity to IR or paclitaxel. Expression of ARTN was enriched in ER-MC cells grown in mammospheric compared with monolayer culture and was also enriched along with BMI1, TWIST1, and DVL1 in mammospheric and ALDH1+ populations. ARTN promoted mammospheric growth and self renewal of ER-MC cells and increased the ALDH1+ population, whereas siRNA-mediated depletion of ARTN diminished these CSC-like cell behaviors. Furthermore, increased ARTN expression was significantly correlated with ALDH1 expression in a cohort of ER-MC patients. Forced expression of ARTN also dramatically enhanced tumor initiating capacity of ER-MC cells in xenograft models at low inoculum. ARTN promotion of the CSC-like cell phenotype was mediated by TWIST1 regulation of BCL-2 expression. ARTN also enhanced mammosphere formation and the ALDH1+ population in estrogen receptor-positive mammary carcinoma (ER+MC) cells. Increased expression of ARTN and the functional consequences thereof may be one common adaptive mechanism used by mammary carcinoma cells to promote cell survival and renewal in hostile tumor microenvironments. [ABSTRACT FROM AUTHOR]

We report herein that trefoil factor 3 (TFF3) is oncogenic and mediates anti-estrogen resistance in human mammary carcinoma. Forced expression of TFF3 in mammary carcinoma cells increased cell proliferation and survival, enhanced anchorage-independent growth, and promoted migration and invasion. Moreover, forced expression of TFF3 increased tumor size in xenograft models. Conversely, depletion of endogenous TFF3 with small interfering RNA (siRNA) decreased the oncogenicity and invasiveness of mammary carcinoma cells. Neutralization of secreted TFF3 by antibody promoted apoptosis, decreased cell growth in vitro, and arrested mammary carcinoma xenograft growth. TFF3 expression was significantly correlated to decreased survival of estrogen receptor (ER)-positive breast cancer patients treated with tamoxifen. Forced expression of TFF3 in mammary carcinoma cells increased ER transcriptional activity, promoted estrogen-independent growth, and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. siRNA-mediated depletion or antibody inhibition of TFF3 significantly enhanced the efficacy of antiestrogens. Increased TFF3 expression was observed in tamoxifen-resistant (TAMR) cells and antibody inhibition of TFF3 in TAMR cells improved tamoxifen sensitivity. Functional antagonism of TFF3 therefore warrants consideration as a novel therapeutic strategy for mammary carcinoma. [ABSTRACT FROM AUTHOR]

Trefoil factors (TFFs), in particular TFF1, are classical estrogen-regulated genes and have served as markers of estrogen gene regulation by various environmental estrogens. TFFs are also regulated by several other factors including growth hormone (hGH), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF) and various oncogenic stimuli. TFFs are secreted proteins present in serum and possess the potential to act as growth factors promoting cell survival, anchorage-independent growth and motility. Recent compelling evidence has emerged from experimental and clinical studies to indicate a pivotal role of TFFs in oncogenic transformation, growth and metastatic extension of common human solid tumours. This review will summarize the current evidence for the involvement of TFFs in human cancer. [Copyright &y& Elsevier]

We herein demonstrate that autocrine human growth hormone production in human mammary carcinoma cells results in increased telomerase activity as a result of specific up-regulation of telomerase catalytic subunit (human telomerase reverse transcriptase (hTERT)) mRNA and protein, This increase in hTERT gene expression is not due to increased transcriptional activation of the hTERT promoter but is the result of increased stability of hTERT mRNA exerted by CU-rich cis-regulatory sequences present in the 3′-untranslated region of TERT mRNA. Autocrine human growth hormone up-regulates two poly(C)-binding proteins, αCP1 and αCP2, which bind to these cis-regulatory elements and stabilize hTERT mRNA. We have therefore demonstrated that post-transcriptional modulation of the level of hTERT mRNA is one mechanism for regulation of cellular telomerase activity. [ABSTRACT FROM AUTHOR]

Forced expression of HOXA1 is sufficient to stimulate oncogenic transformation of immortalized human mammary epithelial cells and subsequent tumor formation. We report here that the expression and transcriptional activity of HOXA1 are increased in mammary carcinoma cells at full confluence. This confluence-dependent expression of HOXA1 was abrogated by incubation of cells with EGTA to produce loss of intercellular contact and rescued by extracellular addition of Ca2+. Increased HOXA1 expression at full confluence was prevented by an E-cadherin function-blocking antibody and attachment of non-confluent cells to a substrate by homophilic ligation of E-cadherin increased HOXA1 expression. E-cadherin-directed signaling increased HOXA1 expression through Rac1. Increased HOXA1 expression consequent to E-cadherin-activated signaling decreased apoptotic cell death and was required for E-cadherin-dependent anchorage-independent proliferation of human mammary carcinoma cells. HOXA1 is therefore a downstream effector of E-cadherin-directed signaling required for anchorage-independent proliferation of mammary carcinoma cells. [ABSTRACT FROM AUTHOR]

We have exploited a discrepancy in the oncogenic potential of autocrine and exogenous human growth hormone (hGH) in an attempt to identify molecules that could potentially be involved in oncogenic transformation of the human mammary epithelial cell. Microarray analysis of 19,000 human genes identified a subset of 305 genes in a human mammary carcinoma cell line that were remarkably different in their response to autocrine and exogenous hGH. Autocrine and exogenous hGH also regulated 167 common genes. Semiquantitative reverse transcription-PCR confirmed differential regulation of genes by either autocrine or exogenous hGH. Functional analysis of one of the identified autocrine hGH-regulated genes, TFF3, determined that its expression is sufficient to support anchorage-independent growth of human mammary carcinoma cells. Small interfering RNA-mediated knockdown of TFF3 concordantly abrogated anchorage-independent growth of mammary carcinoma cells and abrogated the ability of autocrine hGH to stimulate oncogenic transformation of immortalized human mammary epithelial cells. Further functional characterization of the identified subset of specifically autocrine hGH regulated genes will delineate additional novel oncogenes for the human mammary epithelial cell. [ABSTRACT FROM AUTHOR]

Reports that autocrine human growth hormone (hGH) production by human mammary carcinoma cells increases the expression and transcriptional activity of the homeobox domain containing protein HOXA1. Consequence of forced expression of HOXA1 human carcinoma cells; Molecular mechanism by which hGH stimulation of human mammary epithelial cells may result on oncogenic transformation.

Shows that endogenously produced growth hormone-binding protein (GHBP) was able to enhance the STAT5-mediated transcriptional response to growth hormones (GH). Finding that the GHBP exerts divergent effects on STAT5-mediated transcription depending on its cellular location; Factors providing additional mechanisms of transcriptional control.