Autocrine interferon-gamma may affect malignant behavior and sensitivity to tamoxifen of MCF-7 via estrogen receptor beta subtype

Mitogenic actions of estrogens are mediated by two distinct estrogen receptors (ERs), which are critical in the progression and therapeutic response of breast cancer. ER expression is a dynamic phenomenon that is regulated by numerous factors, including cytokines, in the tumor microenvironment. Recently, studies have shown that autocrine production of IL-4 promotes cancer cell growth and there is negative correlation between tumor IL-4 and hormone receptor levels, suggesting that there is crosstalk between cytokine receptors and ER. Thus, we evaluated for interaction between the two ERs and the cytokines IL-4 and IFN-gamma, and if this interaction modulates malignant behavior. We identified that ER beta exerts protective activity in the progression of breast cancer cell line MCF-7, which co-expresses ER alpha and ER beta. IFN-gamma and IL-4 have the opposite effects on malignant biological behavior. Furthermore, we found positive correlation between IFN-gamma and ER beta expression in MCF-7. We also determined that autocrine IFN-gamma in MCF-7 increases mRNA expression of ER beta resulting in enhanced sensitivity to tamoxifen (TAM). These results indicate that ER beta and autocrine IFN-gamma represent two putative targets for breast cancer therapy.