Activation of the estrogen-signaling pathway by p21WAF1/CIP1 in estrogen receptor-negative breast cancer cells

被引:29
作者
Chen, XM
Danes, C
Lowe, M
Herliczek, TW
Keyomarsi, K
机构
[1] Wadsworth Ctr, Div Mol Med, Albany, NY USA
[2] SUNY Albany, Dept Biomed Sci, Albany, NY USA
关键词
D O I
10.1093/jnci/92.17.1403
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 G(1) 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 17 beta-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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页码:1403 / 1413
页数:11
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