Abstract

Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline-inducible transgenic mice that permit Ras activation to be titrated. Low levels of Ras activation — similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2 — stimulate cellular proliferation and mammary epithelial hyperplasias. In contrast, high levels of Ras activation — similar to those found in tumours bearing endogenous Kras2 mutations — induce cellular senescence that is Ink4a–Arf- dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53–Ink4a–Arf-dependent senescence checkpoints.