TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

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 oncogenic RAS requires TGF-β signaling. Suppression of signaling by expression dominant-negative type II receptor, use I receptor inhibitor, or ectopic MYC permitted continued proliferation upon expression. Surprisingly, unlike fibroblasts, shRNA-mediated knockdown ATM CHK2 was unable prevent RAS-mediated OIS, arguing DNA damage is not required for HMEC. Abrogation only allowed HMEC lacking p53 tolerate but also conferred capacity anchorage-independent growth. Thus, after dysregulated provides early barrier malignant progression mediated activation Understanding mechanisms initiate maintain may provide foundation future therapies aimed at reengaging this cancer therapy.