文章基本信息

标题：TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells
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作者：Rocky Cipriano ; Charlene E. Kan ; James Graham 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2011
卷号：108
期号：21
页码：8668-8673
DOI：10.1073/pnas.1015022108
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Oncogene-induced senescence (OIS), the proliferative arrest engaged in response to persistent oncogene activation, serves as an important tumor-suppressive barrier. We show here that finite lifespan human mammary epithelial cells (HMEC) undergo a p16/RB- and p53-independent OIS in response to oncogenic RAS that requires TGF-{beta} signaling. Suppression of TGF-{beta} signaling by expression of a dominant-negative TGF-{beta} type II receptor, use of a TGF-{beta} type I receptor inhibitor, or ectopic expression of MYC permitted continued proliferation upon RAS expression. Surprisingly, unlike fibroblasts, shRNA-mediated knockdown of ATM or CHK2 was unable to prevent RAS-mediated OIS, arguing that the DNA damage response is not required for OIS in HMEC. Abrogation of TGF-{beta} signaling not only allowed HMEC lacking p53 to tolerate oncogenic RAS but also conferred the capacity for anchorage-independent growth. Thus, the OIS engaged after dysregulated RAS expression provides an early barrier to malignant progression and is mediated by TGF-{beta} receptor activation in HMEC. Understanding the mechanisms that initiate and maintain OIS in epithelial cells may provide a foundation for future therapies aimed at reengaging this proliferative barrier as a cancer therapy.
关键词：breast cancer ; tumor suppressor