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Signaling and Regulation

Wilms' Tumor 1 Suppressor Gene Mediates Antiestrogen Resistance via Down-Regulation of Estrogen Receptor- Expression in Breast Cancer Cells

Department of Cellular and Molecular Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

Requests for reprints: Mark D. Minden, Princess Margaret Hospital/Ontario Cancer Institute, University Health Network, Room 5-217, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2015; Fax: 416-946-2082. E-mail: minden{at}uhnres.utoronto.ca

The antiestrogen tamoxifen has been used in the treatment of hormone-responsive breast cancer for over a decade. The loss of estrogen receptor (ER) expression is the most common mechanism for de novo antiestrogen resistance. Wilms' tumor 1 suppressor gene (WT1) is a clinically useful marker that is associated with poor prognosis in breast cancer patients; its high level expression is frequently observed in cases of breast cancer that are estrogen and progesterone receptor negative. The lack of expression of these receptors is characteristic of tumor cells that are not responsive to hormonal manipulation. To determine whether there is a linkage between WT1 expression and antiestrogen resistance in breast cancer cells, we studied the effect of WT1 on tamoxifen responsiveness in ER-positive MCF-7 cells. We found that overexpression of WT1 in MCF-7 markedly abrogated tamoxifen-induced cell apoptosis and 17β-estradiol (E₂)–mediated cell proliferation. The expressions of ER and its downstream target genes were significantly repressed following overexpression of WT1, whereas the down-regulation of WT1 by WT1 shRNA could enhance ER expression and the sensitivity to tamoxifen treatment in ER-negative MDA468 and HCC1954 cells that express high levels of WT1. Furthermore, we have confirmed that the WT1 protein can bind to endogenous WT1 consensus sites in the proximal promoter of ER and thus inhibit the transcriptional activity of the ER promoter in a WT1 site sequence–specific manner. Our study clearly implicates WT1 as a mediator of antiestrogen resistance in breast cancer through down-regulation of ER expression and supports the development of WT1 inhibitors as a potential means of restoring antiestrogen responsiveness in breast cancer therapy. (Mol Cancer Res 2008;6(8):1347–55)