ERβ1 Represses FOXM1 Expression through Targeting ERα to Control Cell Proliferation in Breast Cancer

In this study, we investigated the effects of ectopic estrogen receptor (ER)beta 1 expression in breast cancer cell lines and nude mice xenografts and observed that ER beta 1 expression suppresses tumor growth and represses FOXM1 mRNA and protein expression in ER alpha-positive but not ER alpha-negative breast cancer cells. Furthermore, a significant inverse correlation exists between ER beta 1 and FOXM1 expression at both protein and inRNA transcript levels in ER alpha-positive breast cancer patient samples. Ectopic ER beta 1 expression resulted in decreased FOXM1 protein and mRNA expression only in ERER alpha-positive but not ER alpha-negative breast carcinoma cell lines, suggesting that ER beta 1 represses ER alpha-dependent FOXM1 transcription. Reporter gene assays showed that ER beta 1 represses FOXM1 transcription through an estrogen-response element located within the proximal promoter region that is also targeted by ER alpha. The direct binding of ER beta 1 to the FOXM1 promoter was confirmed by chromatin immunoprecipitation analysis, which also showed that ectopic expression of ER beta 1 displaces ER alpha from the endogenous FOXM1 promoter. Forced expression of ER beta 1 promoted growth suppression in MCF-7 cells, but the anti-proliferative effects of ER beta 1 could be overridden by overexpression of FOXM1, indicating that FOXM1 is an important downstream target of ER beta 1 signaling. Together, these findings define a key anti-proliferative role for ER beta 1 in breast cancer development through negatively regulating FOXM1 expression. (Am J Pathol 2011, 179:1148-1156; DOI: 10.1016/j.ajpath.2011.05 052)