© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 17, 1403-1413,
September 6, 2000
© 2000 Oxford University Press
Activation of the Estrogen-Signaling Pathway by p21WAF1/CIP1 in Estrogen Receptor-Negative Breast Cancer Cells
Affiliations of authors: X. Chen, C. Danes, M. Lowe, T. W. Herliczek, Division of Molecular Medicine, Wadsworth Center, Albany, NY; K. Keyomarsi, Division of Molecular Medicine, Wadsworth Center, and Department of Biomedical Sciences, State University of New York, Albany.
Correspondence to and present address: Khandan Keyomarsi, Ph.D., Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 66, Houston, TX 77030-4095 (e-mail: kkeyomar{at}mdanderson.org).
Background: Estrogen stimulates the proliferation of cells in normal mammary glands and most estrogen receptor (ER)-positive mammary carcinomas by binding to the ER and promoting the transcription of ER-responsive genes. In cells with functional ERs, estrogen mediates the transition of cells from the G1 to S phase of the cell cycle. Several cell cycle regulatory proteins have been implicated in the ER-signaling pathway involved in estrogen-mediated growth stimulation and antiestrogen-mediated growth arrest. We sought to determine whether p21, a cyclin-dependent kinase inhibitor, is a component of this pathway and, if so, whether it can mediate estrogen's action in ER-negative breast cancer cells. Methods: We overexpressed p21 with a tetracycline-inducible system in ER-negative, p21-negative breast cancer cells. Activity of the ER-signaling pathway was monitored in transient transfection assays by using constructs in which the ER promoter or the estrogen-response element (ERE) controls Luciferase expression. The growth-modulating effects of estradiol and antiestrogens on p21-overexpressing clones were assessed. All P values are from two-sided tests. Results: A strong positive association was found between the expression of p21 and ER in nine breast cancer cell lines and in tumor samples from 60 patients with breast cancer (P<.001). Overexpression of p21 in a p21-negative, ER-negative cell line induced both the ER and ERE promoters in an estrogen-responsive manner. Last, stable p21 clones that also lack the expression of wild-type ER were responsive to the growth-inhibitory effects of ICI 182,780, a potent antiestrogen, and the growth-stimulatory effects of 17ß-estradiol. Conclusion: The ability of p21 to mediate the activation of the estrogen-signaling pathway in ER-negative tumor cells suggests that p21 plays a novel role in this pathway, a finding that also has important clinical implications.
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