title: Prognosis of hormone-dependent breast cancers: implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet.
abstract: Estrogen receptor alpha (ERalpha)-positive breast cancers that co-express transcription factors GATA-3 and FOXA1 have a favorable prognosis. These transcription factors form an autoregulatory hormonal network that influences estrogen responsiveness and sensitivity to hormonal therapy. Disruption of this network may be a mechanism whereby ERalpha-positive breast cancers become resistant to therapy. The transcription factor T-bet is a negative regulator of GATA-3 in the immune system. In this study, we report that insulin increases the expression of T-bet in breast cancer cells, which correlates with reduced expression of GATA-3, FOXA1, and the ERalpha:FOXA1:GATA-3 target gene GREB-1. The effects of insulin on GATA-3 and FOXA1 could be recapitulated through overexpression of T-bet in MCF-7 cells (MCF-7-T-bet). Chromatin immunoprecipitation assays revealed reduced ERalpha binding to GREB-1 enhancer regions in MCF-7-T-bet cells and in insulin-treated MCF-7 cells. MCF-7-T-bet cells were resistant to tamoxifen in the presence of insulin and displayed prolonged extracellular signal-regulated kinase and AKT activation in response to epidermal growth factor treatment. ERalpha-positive cells with intrinsic tamoxifen resistance as well as MCF-7 cells with acquired tamoxifen and fulvestrant resistance expressed elevated levels of T-bet and/or reduced levels of FOXA1 and GATA-3. Analysis of publicly available databases revealed ERalpha-positive/T-bet-positive breast cancers expressing lower levels of FOXA1 (P = 0.0137) and GATA-3 (P = 0.0063) compared with ERalpha-positive/T-bet-negative breast cancers. Thus, T-bet expression in primary tumors and circulating insulin levels may serve as surrogate biomarkers to identify ERalpha-positive breast cancers with a dysfunctional hormonal network, enhanced growth factor signaling, and resistance to hormonal therapy.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Kasi
authors.initials: K
authors.lastname: McCune
authors.forename: Poornima
authors.initials: P
authors.lastname: Bhat-Nakshatri
authors.forename: Mangesh A
authors.initials: MA
authors.lastname: Thorat
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Sunil
authors.initials: S
authors.lastname: Badve
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D000077267:Fulvestrant; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D053263:Gene Regulatory Networks; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D011379:Prognosis; D020825:T-Box Domain Proteins / Q000096:biosynthesis* / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
chemical_list: D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D050990:GATA3 Transcription Factor; D051541:Hepatocyte Nuclear Factor 3-alpha; D007328:Insulin; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases