| Abstract: |
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. ©2006 American Association for Cancer Research. |
