ERβ Suppresses TGFβ Signaling via Up regulation of Cystatin Gene Expression to Inhibit Triple Negative Breast Cancer Metastasis

Triple negative breast cancer (TNBC) is an aggressive subtype, with high rates of mortality especially in patients that exhibit chemotherapy resistance. We have shown that approximately 30% of TN breast tumors express estrogen receptor beta (ERβ). In this study, we demonstrate that therapeutic activation of ERβ elicits potent tumor suppressive effects in TNBC. These effects are conferred through the induction of a family of secreted proteins known as the cystatins, which function to inhibit canonical TGFβ signaling, thereby suppressing cancer cell migration and invasion and preventing the development of metastatic lesions in vivo. These data lay the foundation for clinical trials aimed at therapeutically targeting ERβ in TNBC.