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J. Biol. Chem., Vol. 280, Issue 18, 17617-17625, May 6, 2005

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c-Myc Suppresses p21^WAF1/CIP1 Expression during Estrogen Signaling and Antiestrogen Resistance in Human Breast Cancer Cells^*

Shibani Mukherjee and Susan E. Conrad

From the Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan 48824

Estrogen rapidly induces expression of the proto-oncogene c-myc. c-Myc is required for estrogen-stimulated proliferation of breast cancer cells, and deregulated c-Myc expression has been implicated in antiestrogen resistance. In this report, we investigate the mechanism(s) by which c-Myc mediates estrogen-stimulated proliferation and contributes to cell cycle progression in the presence of antiestrogen. The MCF-7 cell line is a model of estrogen-dependent, antiestrogen-sensitive human breast cancer. Using stable MCF-7 derivatives with inducible c-Myc expression, we demonstrated that in antiestrogen-treated cells, the elevated mRNA and protein levels of p21^WAF1/CIP1, a cell cycle inhibitor, decreased upon either c-Myc induction or estrogen treatment. Expression of p21 blocked c-Myc-mediated cell cycle progression in the presence of antiestrogen, suggesting that the decrease in p21 is necessary for this process. Using RNA interference to suppress c-Myc expression, we further established that c-Myc is required for estrogen-mediated decreases in p21^WAF1/CIP1. Finally, we observed that neither c-Myc nor p21^WAF1/CIP1 is regulated by estrogen or antiestrogen in an antiestrogen-resistant MCF-7 derivative. The p21 levels in the antiestrogen-resistant cells increased when c-Myc expression was suppressed, suggesting that loss of p21 regulation was a consequence of constitutive c-Myc expression. Together, these studies implicate p21^WAF1/CIP1 as an important target of c-Myc in breast cancer cells and provide a link between estrogen, c-Myc, and the cell cycle machinery. They further suggest that aberrant c-Myc expression, which is frequently observed in human breast cancers, can contribute to antiestrogen resistance by altering p21^WAF1/CIP1 regulation.

Received for publication, March 1, 2005

^* This study was supported by National Institutes of Health Grant CA76647, Susan G. Komen Breast Cancer Foundation Grant DISS02-1283, and the Schultz Oncology Research Award (to the Michigan State University College of Human Medicine). 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.

To whom correspondence should be addressed: Dept. of Microbiology and Molecular Genetics, 2209 BPS, Michigan State University, East Lansing, MI 48824. Tel.: 517-353-5161; Fax: 517-353-8957; E-mail: conrad{at}msu.edu.

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