Departments of Pathology and Genetics and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Proc Natl Acad Sci U S A. 2011 May 24;108(21):8668-73. doi: 10.1073/pnas.1015022108. Epub 2011 May 9.
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-β signaling. Suppression of TGF-β signaling by expression of a dominant-negative TGF-β type II receptor, use of a TGF-β 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-β 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-β 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.
癌基因诱导的衰老（OIS），即对持续的癌基因激活的增殖抑制，是一种重要的肿瘤抑制屏障。我们在这里表明，有限寿命的人乳腺上皮细胞（HMEC）在响应致癌性 RAS 时会经历 p16/RB 和 p53 不依赖的 OIS，这需要 TGF-β 信号。通过表达显性负 TGF-β 型 II 受体、使用 TGF-β 型 I 受体抑制剂或异位表达 MYC 来抑制 TGF-β 信号，可以在表达 RAS 后继续增殖。令人惊讶的是，与成纤维细胞不同，shRNA 介导的 ATM 或 CHK2 的敲低不能防止 RAS 介导的 OIS，这表明 DNA 损伤反应不是 HMEC 中 OIS 所必需的。阻断 TGF-β 信号不仅允许缺乏 p53 的 HMEC 耐受致癌性 RAS，而且还赋予了锚定独立生长的能力。因此，在失调的 RAS 表达后发生的 OIS 为恶性进展提供了早期屏障，并且在 HMEC 中由 TGF-β 受体激活介导。了解启动和维持上皮细胞中 OIS 的机制可能为未来的治疗方法提供基础，旨在重新激活这种增殖屏障作为癌症治疗。
