In this study, we investigated the regulation of FOXM1 expression by
estrogen receptor alpha (
ERalpha) and its role in hormonal
therapy and endocrine resistance.
FOXM1 protein and
mRNA expression was regulated by ER-
ligands, including
estrogen,
tamoxifen (OHT) and
fulvestrant (
ICI182780; ICI) in
breast carcinoma cell lines. Depletion of
ERalpha by RNA interference (RNAi) in MCF-7 cells downregulated FOXM1 expression. Reporter gene assays showed that
ERalpha activates FOXM1 transcription through an
estrogen-response element (ERE) located within the proximal promoter region. The direct binding of
ERalpha to the FOXM1 promoter was confirmed in vitro by mobility shift and
DNA pull-down assays and in vivo by
chromatin immunoprecipitation (ChIP) analysis. Our data also revealed that upon OHT treatment
ERalpha recruits
histone deacetylases to the ERE site of the FOXM1 promoter, which is associated with a decrease in
histone acetylation and transcription activity. Importantly, silencing of FOXM1 by RNAi abolished
estrogen-induced MCF-7 cell proliferation and overcame acquired
tamoxifen resistance. Conversely, ectopic expression of FOXM1 abrogated the cell cycle arrest mediated by the anti-
estrogen OHT. OHT repressed FOXM1 expression in endocrine sensitive but not resistant
breast carcinoma cell lines. Furthermore, qRT-PCR analysis of
breast cancer patient samples revealed that there was a strong and significant positive correlation between
ERalpha and FOXM1
mRNA expression. Collectively, these results show FOXM1 to be a key mediator of the mitogenic functions of
ERalpha and
estrogen in
breast cancer cells, and also suggest that the deregulation of FOXM1 may contribute to anti-
estrogen insensitivity.