p27Kip1 Repression of ErbB2-Induced Mammary Tumor Growth in Transgenic Mice Involves Skp2 and Wnt/β-Catenin Signaling

Expression of the cyclin-dependent kinase (Cdk) inhibitor (p27Kip1) is frequently reduced in human tumors, often correlating with poor prognosis. p27Kip1 functions as a haploinsufficient tumor suppressor; however, the mechanism by which one allele of p27Kip1 regulates oncogenic signaling in vivo is not well understood. We therefore investigated the mechanisms by which p27Kip1 inhibits mammary tumor onset. Using the common background strain of FVB, p27Kip1 heterozygosity ( p27+/− ) accelerated ErbB2-induced mammary tumorigenesis. We conducted microarray analyses of mammary tumors developing in mice with genetic haploinsufficiency for p27Kip1 expressing a mammary-targeted ErbB2 oncogene. Global gene expression profiling and Western blot analysis of ErbB2/ p27+/− tumors showed that the loss of p27Kip1 induced genes promoting lymphangiogenesis, cellular proliferation, and collaborative oncogenic signaling ( Wnt/β-catenin/Tcf, Cdc25a, Smad7 , and Skp2 ). Skp2 expression was induced by ErbB2 and repressed by p27Kip1. Degradation of p27Kip1 involves an SCF-type E3 ubiquitin ligase, including Skp2. The Skp2 component of the SCFSKP2 complex that degrades p27Kip1 was increased in ErbB2 tumors correlating with earlier tumor onset. In both murine and human ErbB2-overexpressing breast cancers, p27Kip1 levels correlated inversely with Skp2. p27Kip1 haploinsufficiency activated Wnt/β-catenin/hedgehog signaling. Reintroduction of p27Kip1 inhibited β-catenin induction of Tcf-responsive genes ( Siamosis, c-Myc , and Smad7 ). p27Kip1 is haploinsufficient for ErbB2 mammary tumor suppression in vivo and functions to repress collaborative oncogenic signals including Skp2 and Wnt/β-catenin signaling. (Cancer Res 2006; 66(17): 8529-41)