Title | p27Kip1 repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/beta-catenin signaling. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Hulit J, Lee RJ, Li Z, Wang C, Katiyar S, Yang J, Quong AA, Wu K, Albanese C, Russell R, Di Vizio D, Koff A, Thummala S, Zhang H, Harrell J, Sun H, Muller WJ, Inghirami G, Lisanti MP, Pestell RG |
Journal | Cancer Res |
Volume | 66 |
Issue | 17 |
Pagination | 8529-41 |
Date Published | 2006 Sep 01 |
ISSN | 1538-7445 |
Keywords | Animals, beta Catenin, Cell Nucleus, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, DNA Primers, Female, Gene Deletion, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mice, Mice, Inbred Strains, Mice, Knockout, Mice, Transgenic, Polymerase Chain Reaction |
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 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/beta-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/beta-catenin/hedgehog signaling. Reintroduction of p27(Kip1) inhibited beta-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/beta-catenin signaling. |
DOI | 10.1158/0008-5472.CAN-06-0149 |
Alternate Journal | Cancer Res |
PubMed ID | 16951165 |
Grant List | AG20337C / AG / NIA NIH HHS / United States CA14462 / CA / NCI NIH HHS / United States CA536340 / CA / NCI NIH HHS / United States CA76642 / CA / NCI NIH HHS / United States P30 CA56036-08 / CA / NCI NIH HHS / United States R01CA70896 / CA / NCI NIH HHS / United States R01CA75503 / CA / NCI NIH HHS / United States R01CA86072 / CA / NCI NIH HHS / United States R01CA93596 / CA / NCI NIH HHS / United States T32 DK 07513 / DK / NIDDK NIH HHS / United States |
Related Faculty:
Giorgio Inghirami, M.D.