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J. Biol. Chem., Vol. 281, Issue 35, 25167-25176, September 1, 2006

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The Forkhead Box M1 Protein Regulates the Transcription of the Estrogen Receptor in Breast Cancer Cells^*

Patricia A. Madureira, Rana Varshochi, Demetra Constantinidou, Richard E. Francis, R. Charles Coombes, Kwok-Ming Yao, and Eric W.-F. Lam¹

From the Cancer Research-United Kingdom Laboratories, Department of Oncology, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom, Department of Biochemistry, The University of Hong Kong, 3/F Laboratory Block, The Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, China

In this study, we have identified the Forkhead transcription factor FoxM1 as a physiological regulator of estrogen receptor (ER) expression in breast carcinoma cells. Our survey of a panel of 16 different breast cell lines showed a good correlation (13/16) between FoxM1 expression and expression of ER at both protein and mRNA levels. We have also demonstrated that ectopic expression of FoxM1 in two different estrogen receptor-positive breast cancer cell lines, MCF-7 and ZR-75–30, led to up-regulation of ER expression at protein and transcript levels. Furthermore, treatment of MCF-7 cells with the MEK inhibitor U0126, which blocks ERK1/2-dependent activation of FoxM1, also repressed ER expression. Consistent with this, silencing of FoxM1 expression in MCF-7 cells using small interfering RNA resulted in the almost complete abrogation of ER expression. We also went on to show that FoxM1 can activate the transcriptional activity of human ER promoter primarily through two closely located Forkhead response elements located at the proximal region of the ER promoter. Chromatin immunoprecipitation and biotinylated oligonucleotide pulldown assays have allowed us to confirm these Forkhead response elements as important for FoxM1 binding. Further co-immunoprecipitation experiments showed that FoxO3a and FoxM1 interact in vivo. Together with the chromatin immunoprecipitation and biotinylated oligonucleotide pulldown data, the co-immunoprecipitation results also suggest the possibility that FoxM1 and FoxO3a cooperate to regulate ER gene transcription.

Received for publication, April 24, 2006 , and in revised form, June 28, 2006.

^* This work was supported by grants from Cancer Research United Kingdom, the Association for International Cancer Research, Leukemia Research Fund, Medical Research Council, Engineering and Physical Sciences Research Council, Fundação para a Ciência e a Tecnologia (Portugal), and the Research Grants Council of the Hong Kong Special Administrative Region (China) (HKU 7650/05M). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ To whom correspondence should be addressed. Tel.: 44-20-8383-5829; Fax: 44-20-8383-5830; E-mail: eric.lam{at}imperial.ac.uk.

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