A prostatic intraepithelial neoplasia-dependent p27Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression

被引：147

作者：

Majumder, Pradip K. ^{[1
,2
]}

Grisanzio, Chiara ^{[3
]}

O'Connell, Fionnuala ^{[1
,3
]}

Barry, Marc ^{[3
]}

Brito, Joseph M. ^{[1
]}

Xu, Qing ^{[1
,2
]}

Guney, Isil ^{[1
,2
]}

Berger, Raanan ^{[1
,2
]}

Herman, Paula ^{[1
,2
]}

Bikoff, Rachel ^{[1
,2
]}

Fedele, Giuseppe ^{[1
,3
]}

Baek, Won-Ki ^{[1
,2
]}

Wang, Shunyou ^{[4
]}

Ellwood-Yen, Katharine ^{[4
]}

Wu, Hong ^{[4
]}

Sawyers, Charles L. ^{[5
,6
]}

Signoretti, Sabina

Hahn, William C. ^{[1
,2
,7
]}

Loda, Massimo ^{[1
,2
,3
,7
]}

Sellers, William R. ^{[1
,2
,8
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[5] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA

[7] MIT, Borad Inst, Cambridge, MA 02142 USA

[8] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

来源：

CANCER CELL | 2008年 / 14卷 / 02期

关键词：

D O I：

10.1016/j.ccr.2008.06.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：146 / 155

页数：10

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