Can Diabetes Change the Intrinsic Subtype Specificity of Breast Cancer

Estrogen receptor alpha ER alpha-positive breast cancers that co-express transcription factors GATA-3 and FOXA1 have a favorable prognosis. These transcription factors influence estrogen responsiveness and sensitivity to hormonal therapy. Disruption of this network may be a mechanism whereby ER alpha positive breast cancers become resistant to therapy. The transcription factor T-bet is a negative regulator of GATA-3 in the immune system. We report that insulin increases the expression of T-bet in breast cancer cells, which correlates with reduced expression of GATA-3 and FOXA1. 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. MCF-7-T-bet cells were resistant to tamoxifen and displayed prolonged ERK and AKT activation in response to epidermal growth factor treatment. ER alpha-positiveT-bet-positive primary breast cancers express lower levels of FOXA1 p0.0137 and GATA-3 p0.0063 compared to ER alpha-positiveT-betnegative breast cancers. Thus, T-bet expression and circulating insulin levels may serve as surrogate biomarkers to analyze progression of identify ER alpha-positive breast cancer cancer.