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p27^Kip1 Repression of ErbB2-Induced Mammary Tumor Growth in Transgenic Mice Involves Skp2 and Wnt/ß-Catenin Signaling

¹ Department of Developmental and Molecular Biology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York; ² Kimmel Cancer Center, Departments of Cancer Biology and Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania; ³ Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; ⁴ Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute; ⁵ Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York; ⁶ Department of Genetics, Yale University School of Medicine, New Haven, Connecticut; and ⁷ Molecular Oncology Labs, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada

Requests for reprints: Richard G. Pestell, Departments of Cancer Biology and Medical Oncology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107. Phone: 215-503-5649; Fax: 215-923-9334; E-mail: Richard.Pestell{at}jefferson.edu or D_Scardino{at}mail.jci.tju.edu.

Expression of the cyclin-dependent kinase (Cdk) inhibitor (p27^Kip1) is frequently reduced in human tumors, often correlating with poor prognosis. p27^Kip1 functions as a haploinsufficient tumor suppressor; however, the mechanism by which one allele of p27^Kip1 regulates oncogenic signaling in vivo is not well understood. We therefore investigated the mechanisms by which p27^Kip1 inhibits mammary tumor onset. Using the common background strain of FVB, p27^Kip1 heterozygosity (p27^+/–) accelerated ErbB2-induced mammary tumorigenesis. We conducted microarray analyses of mammary tumors developing in mice with genetic haploinsufficiency for p27^Kip1 expressing a mammary-targeted ErbB2 oncogene. Global gene expression profiling and Western blot analysis of ErbB2/p27^+/– tumors showed that the loss of p27^Kip1 induced genes promoting lymphangiogenesis, cellular proliferation, and collaborative oncogenic signaling (Wnt/ß-catenin/Tcf, Cdc25a, Smad7, and Skp2). Skp2 expression was induced by ErbB2 and repressed by p27^Kip1. Degradation of p27^Kip1 involves an SCF-type E3 ubiquitin ligase, including Skp2. The Skp2 component of the SCF^SKP2 complex that degrades p27^Kip1 was increased in ErbB2 tumors correlating with earlier tumor onset. In both murine and human ErbB2-overexpressing breast cancers, p27^Kip1 levels correlated inversely with Skp2. p27^Kip1 haploinsufficiency activated Wnt/ß-catenin/hedgehog signaling. Reintroduction of p27^Kip1 inhibited ß-catenin induction of Tcf-responsive genes (Siamosis, c-Myc, and Smad7). p27^Kip1 is haploinsufficient for ErbB2 mammary tumor suppression in vivo and functions to repress collaborative oncogenic signals including Skp2 and Wnt/ß-catenin signaling. (Cancer Res 2006; 66(17): 8529-41)

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