The retinoblastoma gene Rb and its family member p130 suppress lung adenocarcinoma induced by oncogenic K-Ras

Abstract

Mutations of the retinoblastoma tumor suppressor gene RB are frequently observed in human cancers, but rarely in non-small cell lung carcinomas (NSCLCs). Emerging evidence also suggests that the RB-related gene p130 is inactivated in a subset of human NSCLCs. To directly test the specific tumor suppressor roles of RB and p130 in NSCLC, we crossed Rb and p130 conditional mutant mice to mice carrying a conditional oncogenic K-Ras allele. In this model, controlled oncogenic K-Ras activation leads to the development of adenocarcinoma, a major subtype of NSCLC. We found that loss of p130 accelerated the death of mice, providing direct evidence in vivo that p130 is a tumor suppressor gene, albeit a weak one in this context. Loss of Rb increased the efficiency of lung cancer initiation and resulted in the development of high-grade adenocarcinomas and rapid death. Thus, despite the low frequency of RB mutations in human NSCLCs and reports that K-Ras activation and loss of RB function are rarely found in the same human tumors, loss of Rb clearly cooperates with activation of oncogenic K-Ras in lung adenocarcinoma development in mice.

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

“…Thus, the genetic milieu and tissue context are both likely modifiers of the interactions between RB and oncogenic pathways. Our studies focused on exacerbation of existing tumorigenic phenotypes-that is, disease progression, and in this context are consistent with several animal models of Ras-mediated tumorigenesis wherein RB loss exacerbates the tumor phenotype Ho et al, 2009). Particularly, in a two-stage chemical skin carcinogenesis model, induction of DNA-damage response by direct carcinogen (DMBA) exposure or Ras activation was shown to increase the rates of acute p53-mediated apoptosis in an RB-deficient setting, ultimately limiting disease initiation (Ruiz et al, 2005;Lara et al, 2008;Santos et al, 2008).…”

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

“…However, introduction of mutant Ras into wild-type primary cells leads to tumoursuppressing oncogene-induced senescence mediated by activation of the Rb1 family of cell cycle inhibitors 34 . Accordingly, the Rb1 family represents a barrier to the development of lung adenocarcinoma in Ras LA1 mice 35 . Therefore, Rb1 is either mutated (rarely, primarily retinoblastoma and small cell lung cancer) or inactivated by deregulated cyclin-dependent kinase hyperphosphorylation (in most other tumours) in cancer 36 .…”

Sequential Inductions of the ZEB1 Transcription Factor Caused by Mutation of Rb and Then Ras Proteins Are Required for Tumor Initiation and Progression

“…Instead, in most tumors the Rb1 family is inactivated by hyperphosphorylation resulting from deregulated cyclin-dependent kinase (cdk) activity (1,2), and such loss of the Rb1 pathway is a hallmark of cancer; it reverses cell contact inhibition to allow tumor outgrowth, and it leads to immortalization of MEFs (2-7). Induction of senescence by Rb1 blocks proliferation of cells harboring activating Ras mutations (oncogene-induced senescence); thus, inactivation of the Rb1 pathway removes a barrier to Ras mutation in vivo (5,6,8,9). Ras mutation becomes sufficient for tumor initiation when the Rb1 pathway is mutated in MEFs (6), demonstrating that Ras and Rb1 comprise two opposing arms of a cancer initiation axis.…”