期刊
CANCER CELL
卷 14, 期 2, 页码 146-155出版社
CELL PRESS
DOI: 10.1016/j.ccr.2008.06.002
关键词
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资金
- Linda and Arthur Gelb Center for Translational Research
- National Cancer Institute [K01 CA94223, PO1 CA89021]
- Prostate Cancer Foundation
- Damon Runyon Cancer Research Foundation
- DF/HCC Prostate Cancer SPORE
- Novartis Institutes for BioMedical Research
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.
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