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J. Biol. Chem., Vol. 281, Issue 36, 26587-26601, September 8, 2006

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BRCA1 Suppresses Osteopontin-mediated Breast Cancer^*

Mohamed K. El-Tanani¹, Frederick Charles Campbell, Paul Crowe, Pauline Erwin, Denis Paul Harkin, Paul Pharoah, Bruce Ponder, and Philip S. Rudland^¶

From the Centre for Cancer Research and Cell Biology, Queen's University Belfast, Grosvenor Road, Belfast BT12 6BJ, Northern Ireland, United Kingdom, Strangeways Research Laboratory, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom, and ^¶Cancer and Polio Research Fund Laboratories, School of Biological Sciences, University of Liverpool, P. O. Box 147, Liverpool L69 7ZB, United Kingdom

BRCA1 is a well described breast cancer susceptibility gene thought to be involved primarily in DNA repair. However, mutation within the BRCA1 transcriptional domain is also implicated in neoplastic transformation of mammary epithelium, but responsible mechanisms are unclear. Here we show in a rat mammary model system that wild type (WT) BRCA1 specifically represses the expression of osteopontin (OPN), a multifunctional estrogen-responsive gene implicated in oncogenic transformation, particularly that of the breast. WT.BRCA1 selectively binds OPN-activating transcription factors estrogen receptor , AP-1, and PEA3, inhibits OPN promoter transactivation, and suppresses OPN mRNA and protein both from an endogenous gene and a relevant model inducible gene. WT.BRCA1 also inhibits OPN-mediated neoplastic transformation characterized by morphology change, anchorage-independent growth, adhesion to fibronectin, and invasion through Matrigel. A mutant BRCA1 allele (Mut.BRCA1) associated with familial breast cancer lacks OPN suppressor effects, binds to WT.BRCA1, and impedes WT.BRCA1 suppression of OPN. Stable transfection of rat breast tumor cell lines with Mut.BRCA1 dramatically up-regulates OPN protein and induces anchorage independent growth. In human primary breast cancer, BRCA1 mutation is significantly associated with OPN overexpression. Taken together, these data suggest that BRCA1 mutation may confer increased tissue-specific cancer risk, in part by disruption of BRCA1 suppression of OPN gene transcription.

Received for publication, May 9, 2006 , and in revised form, June 26, 2006.

^* This work was supported by Royal Victoria Hospital Research Fund, Belfast, UK, and the Cancer and Polio Research Fund. 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 additional text and supplemental Fig. 1.

¹ To whom correspondence and reprints requests should be addressed. Tel.: 44-28-90-632528; Fax: 44-28-321811; E-mail: m.el-tanani{at}qub.ac.uk.

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