PMID- 28745322
DCOM- 20171201
LR  - 20180512
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 36
IP  - 45
DP  - 2017 Nov 9
TI  - p53 loss does not permit escape from Braf(V600E)-induced senescence in a mouse
      model of lung cancer.
PG  - 6325-6335
LID - 10.1038/onc.2017.235 [doi]
AB  - 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). Braf(V600E) expression induces benign
      lung adenomas that fail to progress to adenocarcinoma because of oncogene-induced
      senescence (OIS). Braf(V600E) 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 (Braf(V600E)
      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 Braf(V600E) induced senescence is irreversible in vivo and suggests that
      therapy-induced senescence would halt further tumor progression.
FAU - Garnett, S
AU  - Garnett S
AD  - Department of Biology, McGill University, Montreal, QC, Canada.
FAU - Dutchak, K L
AU  - Dutchak KL
AD  - Department of Biology, McGill University, Montreal, QC, Canada.
FAU - McDonough, R V
AU  - McDonough RV
AD  - Department of Biology, McGill University, Montreal, QC, Canada.
FAU - Dankort, D
AU  - Dankort D
AD  - Department of Biology, McGill University, Montreal, QC, Canada.
AD  - Goodman Cancer Research Centre, Montreal, QC, Canada.
LA  - eng
GR  - MOP-97925/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170724
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC (Braf protein, mouse)
RN  - EC (Proto-Oncogene Proteins B-raf)
RN  - Adenocarcinoma of lung
SB  - IM
MH  - Adenocarcinoma/*genetics/metabolism/pathology
MH  - Adenoma/genetics/metabolism/pathology
MH  - Animals
MH  - Cellular Senescence/genetics
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Lung Neoplasms/*genetics/metabolism/pathology
MH  - Mice
MH  - Proto-Oncogene Proteins B-raf/*genetics/metabolism
MH  - Tumor Suppressor Protein p53/*deficiency/genetics/metabolism
EDAT- 2017/07/27 06:00
MHDA- 2017/12/02 06:00
CRDT- 2017/07/27 06:00
PHST- 2017/01/17 00:00 [received]
PHST- 2017/05/26 00:00 [revised]
PHST- 2017/06/08 00:00 [accepted]
PHST- 2017/07/27 06:00 [pubmed]
PHST- 2017/12/02 06:00 [medline]
PHST- 2017/07/27 06:00 [entrez]
AID - onc2017235 [pii]
AID - 10.1038/onc.2017.235 [doi]
PST - ppublish
SO  - Oncogene. 2017 Nov 9;36(45):6325-6335. doi: 10.1038/onc.2017.235. Epub 2017 Jul