p27^Kip1 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 (p27 ^Kip1) is frequently reduced in human tumors, often correlating with poor prognosis. p27^Kip1 functions as a haplo-insufficient 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/β-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/β-catenin/hedgehog signaling. Reintroduction of p27^Kip1 inhibited β-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/β-catenin signalling.