FOXM1 is a transcriptional target of ERα and has a critical role in breast cancer endocrine sensitivity and resistance

Title: FOXM1 is a transcriptional target of ERα and has a critical role in breast cancer endocrine sensitivity and resistance
Authors: Millour, J
Constantinidou, D
Stavropoulou, AV
Wilson, MSC
Myatt, SS
Kwok, JM-M
Sivanandan, K
Coombes, RC
Medema, RH
Hartman, J
Lykkesfeldt, AE
Lam, EW-F
Item Type: Journal Article
Abstract: In this study, we investigated the regulation of FOXM1 expression by estrogen receptor α (ERα) 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 ERα by RNA interference (RNAi) in MCF-7 cells downregulated FOXM1 expression. Reporter gene assays showed that ERα activates FOXM1 transcription through an estrogen-response element (ERE) located within the proximal promoter region. The direct binding of ERα 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 ERα 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 ERα and FOXM1 mRNA expression. Collectively, these results show FOXM1 to be a key mediator of the mitogenic functions of ERα and estrogen in breast cancer cells, and also suggest that the deregulation of FOXM1 may contribute to anti-estrogen insensitivity.
Issue Date: 8-Mar-2010
Date of Acceptance: 29-Jan-2010
URI: http://hdl.handle.net/10044/1/39182
DOI: http://dx.doi.org/10.1038/onc.2010.47
ISSN: 1476-5594
Publisher: Nature Publishing Group
Start Page: 2983
End Page: 2995
Journal / Book Title: Oncogene
Volume: 29
Issue: 20
Copyright Statement: © 2010 Macmillan Publishers Limited. All rights reserved.
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C37/A12011
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
GENETICS & HEREDITY
ONCOLOGY
breast cancer
forkhead
estrogen receptor
FOXM1
endocrine resistance
transcription
ESTROGEN-RECEPTOR-ALPHA
CYCLIN D1
HEPATOCYTE ENTRY
REGULATED GENES
FACTOR HFH-11B
GROWTH-FACTOR
CELL-LINES
S-PHASE
EXPRESSION
MOUSE
Blotting, Western
Breast Neoplasms
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Chromatin Immunoprecipitation
Drug Resistance, Neoplasm
Electrophoretic Mobility Shift Assay
Estradiol
Estrogen Antagonists
Estrogen Receptor alpha
Estrogens
Female
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Humans
Mutagenesis, Site-Directed
Promoter Regions, Genetic
RNA, Messenger
Response Elements
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Cell Line, Tumor
Tumor Cells, Cultured
Humans
Breast Neoplasms
Estradiol
Estrogen Antagonists
Estrogen Receptor alpha
RNA, Messenger
Estrogens
Blotting, Western
Electrophoretic Mobility Shift Assay
Chromatin Immunoprecipitation
Mutagenesis, Site-Directed
Reverse Transcriptase Polymerase Chain Reaction
Cell Cycle
Cell Proliferation
Gene Expression Regulation, Neoplastic
Response Elements
Drug Resistance, Neoplasm
Female
Forkhead Transcription Factors
Promoter Regions, Genetic
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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