Diminished WNT → β-catenin → c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors

  1. Martin McMahon1,2,7
  1. 1Helen Diller Family Comprehensive Cancer Center,
  2. 2Department of Cell and Molecular Pharmacology,
  3. 3Department of Pathology, University of California at San Francisco, San Francisco, California 94158, USA;
  4. 4Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
    1. 5 These authors contributed equally to this work.

    • 6 Present address: Astellas Pharma, Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.

    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.

    Keywords

    Footnotes

    • Received October 28, 2013.
    • Accepted January 30, 2014.

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