Diminished WNT → β-catenin → c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors
- Joseph Juan1,2,5,
- Teruyuki Muraguchi1,2,5,6,
- Gioia Iezza3,
- Rosalie C. Sears4 and
- Martin McMahon1,2,7
- 1Helen Diller Family Comprehensive Cancer Center,
- 2Department of Cell and Molecular Pharmacology,
- 3Department of Pathology, University of California at San Francisco, San Francisco, California 94158, USA;
- 4Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
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↵5 These authors contributed equally to this work.
Abstract
Oncogene-induced senescence (OIS) is proposed as a cellular defense mechanism that restrains malignant progression of oncogene-expressing, initiated tumor cells. Consistent with this, expression of BRAFV600E in the mouse lung epithelium elicits benign tumors that fail to progress to cancer due to an apparent senescence-like proliferative arrest. Here we demonstrate that nuclear β-catenin → c-MYC signaling is essential for early stage proliferation of BRAFV600E-induced lung tumors and is inactivated in the subsequent senescence-like state. Furthermore, either β-catenin silencing or pharmacological blockade of Porcupine, an acyl-transferase essential for WNT ligand secretion and activity, significantly inhibited BRAFV600E-initiated lung tumorigenesis. Conversely, sustained activity of β-catenin or c-MYC significantly enhanced BRAFV600E-induced lung tumorigenesis and rescued the anti-tumor effects of Porcupine blockade. These data indicate that early stage BRAFV600E-induced lung tumors are WNT-dependent and suggest that inactivation of WNT → β-catenin → c-MYC signaling is a trigger for the senescence-like proliferative arrest that constrains the expansion and malignant progression of BRAFV600E-initiated lung tumors. Moreover, these data further suggest that the trigger for OIS in initiated BRAFV600E-expressing lung tumor cells is not simply a surfeit of signals from oncogenic BRAF but an insufficiency of WNT → β-catenin → c-MYC signaling. These data have implications for understanding how genetic abnormalities cooperate to initiate and promote lung carcinogenesis.
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Footnotes
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↵7 Corresponding author
E-mail mcmahon{at}cc.ucsf.edu
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.233627.113.
- Received October 28, 2013.
- Accepted January 30, 2014.
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