Can Diabetes Change the Intrinsic Subtype Specificity of Breast Cancer

摘要

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-positive/T-bet-positive primary breast cancers express lower levels of FOXA1 (p=0.0137) and GATA-3 (p=0.0063) compared to ER alpha-positive/T-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.