ER?1 represses FOXM1 expression through targeting ER? to control cell proliferation in breast cancer.

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

SUBMITTER: Horimoto Y 

PROVIDER: S-EPMC3157253 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature