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J. Biol. Chem., Vol. 278, Issue 42, 41355-41366, October 17, 2003

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Estrogens Down-regulate p27^Kip1 in Breast Cancer Cells through Skp2 and through Nuclear Export Mediated by the ERK Pathway^*

James S. Foster , Romaine I. Fernando , Noriko Ishida , Keiichi I. Nakayama  and Jay Wimalasena  ¶

From the Department of Obstetrics and Gynecology, Graduate School of Medicine, Program in Comparative and Experimental Medicine, University of Tennessee Medical Center, Knoxville, Tennessee 37920 and the Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan

The cyclin-dependent kinase (CDK) inhibitor p27^Kip1 plays a key role in growth and development of the mammary epithelium and in breast cancer. p27^Kip1 levels are regulated through ubiquitin/proteasome-mediated proteolysis, promoted by CDK2 and the F box protein Skp2 at the G₁/S transition, and independent of Skp2 in mid-G₁. We investigated the respective roles of Skp2 and subcellular localization of p27^Kip1 in down-regulation of p27^Kip1 induced in MCF-7 cells by estrogens. 17-Estradiol treatment increased Skp2 expression in MCF-7 cells; however, this increase was prevented by G₁ blockade mediated by p16^Ink4a or the CDK inhibitor roscovitine, whereas down-regulation of p27^Kip1 was maintained. Exogenous Skp2 prevented growth arrest of MCF-7 cells by antiestrogen, coinciding with decreased p27^Kip1 expression. Under conditions of G₁ blockade, p27^Kip1 was stabilized by inhibition of CRM1-dependent nuclear export with leptomycin B or by mutation of p27^Kip1 (Ser¹⁰ Ala; S10A) interfering with CRM1/p27^Kip1 interaction. Antisense Skp2 oligonucleotides and a dominant-interfering Cul-1(1–452) mutant prevented down-regulation of p27^Kip1S10A, whereas Skp2 overexpression elicited its destruction in mitogen-deprived cells. Active mediators of the extracellular signal-regulated kinase (ERK) pathway including Raf-1^caax induced cytoplasmic localization of p27^Kip1 in antiestrogen-treated cells and prevented accumulation of p27^Kip1 in these cells independent of Skp2 expression and coinciding with ERK activation. Genetic or chemical blockade of the ERK pathway prevented down-regulation and cytoplasmic localization of p27^Kip1 in response to estrogen. Our studies indicate that estrogens elicit down-regulation of p27^Kip1 in MCF-7 cells through Skp2-dependent and -independent mechanisms that depend upon subcellular localization of p27^Kip1 and require the participation of mediators of the Ras/Raf-1/ERK signaling pathway.

Received for publication, March 19, 2003 , and in revised form, July 29, 2003.

^* This work was supported by Grant CA84048 from the NCI, National Institutes of Health. 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 Obstetrics and Gynecology, Graduate School of Medicine, Program in Comparative and Experimental Medicine, University of Tennessee Medical Center, 1924 Alcoa Highway, Knoxville, TN 37920. Tel.: 865-544-8961; Fax: 865-544-6863; E-mail: jwimalas{at}utk.edu.

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