title: A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression.
abstract: Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27(Kip1) upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27(Kip1)-driven checkpoint limits progression of PIN to CaP.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Majumder
authors.forename: Chiara
authors.initials: C
authors.lastname: Grisanzio
authors.forename: Fionnuala
authors.initials: F
authors.lastname: O'Connell
authors.forename: Marc
authors.initials: M
authors.lastname: Barry
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Brito
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Isil
authors.initials: I
authors.lastname: Guney
authors.forename: Raanan
authors.initials: R
authors.lastname: Berger
authors.forename: Paula
authors.initials: P
authors.lastname: Herman
authors.forename: Rachel
authors.initials: R
authors.lastname: Bikoff
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fedele
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Baek
authors.forename: Shunyou
authors.initials: S
authors.lastname: Wang
authors.forename: Katharine
authors.initials: K
authors.lastname: Ellwood-Yen
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
mesh_terms: D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002460:Cell Line; D016764:Cell Polarity; D049109:Cell Proliferation; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases
chemical_list: D015415:Biomarkers; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases