p27Kip1 repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/beta-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 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.
Hulit
James
J
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
Lee
Richard J
RJ
Li
Zhiping
Z
Wang
Chenguang
C
Katiyar
Sanjay
S
Yang
Jianguo
J
Quong
Andrew A
AA
Wu
Kongming
K
Albanese
Chris
C
Russell
Robert
R
Di Vizio
Dolores
D
Koff
Andrew
A
Thummala
Saiinder
S
Zhang
Hui
H
Harrell
Jennifer
J
Sun
Hong
H
Muller
William J
WJ
Inghirami
Giorgio
G
Lisanti
Michael P
MP
Pestell
Richard G
RG
D000818:Animals; D002467:Cell Nucleus / Q000502:physiology / Q000648:ultrastructure; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D005260:Female; D017353:Gene Deletion; D008321:Mammary Glands, Animal / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D051176:beta Catenin / Q000502:physiology*
C495267:CTNNB1 protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D051176:beta Catenin; D050760:Cyclin-Dependent Kinase Inhibitor p27