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Signaling and Regulation

ERß Sensitizes Breast Cancer Cells to Retinoic Acid: Evidence of Transcriptional Crosstalk¹

Departments of Oncology and Medicine, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital and McGill University, Montreal, Quebec, Canada

Requests for reprints: Wilson H. Miller Jr., Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, 3755 Cote Sainte Catherine Road, Montreal, Quebec, Canada H3T 1E2. Phone: 514-340-8222, ext. 4365; Fax: 514-340-7576. E-mail: wmiller{at}ldi.jgh.mcgill.ca

The ability of retinoids to inhibit breast cancer cell growth correlates with estrogen receptor (ER) status, as shown by the antiproliferative effects of retinoids in ER-positive breast cancer cells and their use as chemopreventive agents in premenopausal women. The discovery of ERß, also present in breast cancer cells, has added a new level of complexity to this malignancy. To determine the retinoid response in ERß-expressing breast cancer cells, we used retroviral transduction of ERß in ER-negative MDA-MB-231 cells. Western blot and immunofluorescence confirmed expression and nuclear localization of ERß, whereas functionality was shown using an estrogen response element–containing reporter. A significant retinoic acid (RA)–mediated growth inhibition was observed in the transduced ERß-positive cells as shown by proliferation assays. Addition of estradiol, tamoxifen, or ICI 182,780 had no effect on cell growth and did not alter RA sensitivity. We observed that retinoids altered ERß-mediated transcriptional activity from an estrogen response element, which was confirmed by decreased expression of the pS2 gene, and from an activator protein response element. Conversely, the expression of ERß altered RA receptor (RAR) ß expression, resulting in greater induction of RARß gene expression on RA treatment, without altered expression of RAR. Our data provide evidence of transcriptional crosstalk between ERß and RAR in ERß-positive breast cancer cells that are growth inhibited by RA.

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