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Oncogene. 2017 Nov 9;36(45):6325-6335. doi: 10.1038/onc.2017.235. Epub 2017 Jul 24.

p53 loss does not permit escape from BrafV600E-induced senescence in a mouse model of lung cancer.

Author information

1
Department of Biology, McGill University, Montréal, QC, Canada.
2
Goodman Cancer Research Centre, Montréal, QC, Canada.

Abstract

Lung cancer arises through the acquisition of a number of genetic lesions, with a preponderance of activating mutations in the canonical mitogen-activated protein kinase (MAPK) cascade (RTK-RAS-RAF-MEK). BrafV600E expression induces benign lung adenomas that fail to progress to adenocarcinoma because of oncogene-induced senescence (OIS). BrafV600E expression, coupled with simultaneous p53 ablation, permits bypass of senescence and progression to lung adenocarcinoma. However, spontaneous human tumors sustain mutations in a temporally separated manner. Here, we use a mouse lung cancer model where oncogene activation (BrafV600E expression) and tumor suppressor loss (p53 ablation) are independently controlled through the actions of Flp and Cre recombinase, respectively. We show that p53 loss before OIS is permissive for the transition from lung adenoma to adenocarcinoma. In contrast, p53 loss after senescence is established fails to enable escape from senescence and disease progression. This study demonstrates that BrafV600E induced senescence is irreversible in vivo and suggests that therapy-induced senescence would halt further tumor progression.

PMID:
28745322
DOI:
10.1038/onc.2017.235
[Indexed for MEDLINE]

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