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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

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ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer.

Horimoto Yoshiya Y Hartman Johan J Millour Julie J Pollock Steven S Olmos Yolanda Y Ho Ka-Kei KK Coombes R Charles RC Poutanen Matti M Mäkelä Sari I SI El-Bahrawy Mona M Speirs Valerie V Lam Eric W-F EW

The American journal of pathology 20110716 3

In this study, we investigated the effects of ectopic estrogen receptor (ER)β1 expression in breast cancer cell lines and nude mice xenografts and observed that ERβ1 expression suppresses tumor growth and represses FOXM1 mRNA and protein expression in ERα-positive but not ERα-negative breast cancer cells. Furthermore, a significant inverse correlation exists between ERβ1 and FOXM1 expression at both protein and mRNA transcript levels in ERα-positive breast cancer patient samples. Ectopic ERβ1 ex ...[more]

PMID: 21763263

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Project description:BackgroundLiver Receptor Homolog 1 (LRH-1, NR5A2) is an orphan nuclear receptor that is over-expressed in cancers in tissues such as the breast, colon and pancreas. LRH-1 plays important roles in embryonic development, steroidogenesis and cholesterol homeostasis. In tumor cells, LRH-1 induces proliferation and cell cycle progression. High LRH-1 expression is demonstrated in breast cancers, positively correlating with ERα status and aromatase activity. LRH-1 dependent cellular mechanisms in breast cancer epithelial cells are poorly defined. Hence in the present study we investigated the actions of LRH-1 in estrogen receptor α (ERα) positive breast cancer cells.ResultsThe study aimed to investigate LRH-1 dependent mechanisms that promote breast cancer proliferation. We identified that LRH-1 regulated the expression of Growth Regulation by Estrogen in Breast Cancer 1 (GREB1) in MCF-7 and MDA-MB-231 cells. Over-expression of LRH-1 increased GREB1 mRNA levels while knockdown of LRH-1 reduced its expression. GREB1 is a well characterised ERα target gene, with three estrogen response elements (ERE) located on its promoter. Chromatin immunoprecipitation studies provided evidence of the co-localisation of LRH-1 and ERα at all three EREs. With electrophoretic mobility shift assays, we demonstrated direct binding of LRH-1 to EREs located on GREB1 and Trefoil Factor 1 (TFF1, pS2) promoters. LRH-1 and ERα co-operatively activated transcription of ERE luciferase reporter constructs suggesting an overlap in regulation of target genes in breast cancer cells. Over-expression of LRH-1 resulted in an increase in cell proliferation. This effect was more pronounced with estradiol treatment. In the presence of ICI 182,780, an ERα antagonist, LRH-1 still induced proliferation.ConclusionsWe conclude that in ER-positive breast cancer cells, LRH-1 promotes cell proliferation by enhancing ERα mediated transcription of target genes such as GREB-1. Collectively these findings indicate the importance of LRH-1 in the progression of hormone-dependent breast cancer and implicate LRH-1 as a potential avenue for drug development.

Dataset Information

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

Publications

ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer.

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