MYC Suppresses Cancer Metastasis by Direct Transcriptional Silencing of αv and β3 Integrin Subunits

Nat Cell Biol. 2012 May 13;14(6):567-74. doi: 10.1038/ncb2491.

Abstract

Overexpression of MYC transforms cells in culture, elicits malignant tumours in experimental animals and is found in many human tumours. We now report the paradoxical finding that this powerful oncogene can also act as a suppressor of cell motility, invasiveness and metastasis. Overexpression of MYC stimulated proliferation of breast cancer cells both in culture and in vivo as expected, but inhibited motility and invasiveness in culture, and lung and liver metastases in xenografted tumours. We show further that MYC represses transcription of both subunits of αvβ3 integrin, and that exogenous expression of β3 integrin in human breast cancer cells that do not express this integrin rescues invasiveness and migration when MYC is downregulated. These data uncover an unexpected function of MYC, provide an explanation for the hitherto puzzling literature on the relationship between MYC and metastasis, and reveal a variable that could influence the development of therapies that target MYC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Extracellular Matrix / metabolism
  • Gene Silencing
  • Humans
  • Integrin alpha5 / genetics
  • Integrin alpha5 / metabolism*
  • Integrin beta3 / genetics
  • Integrin beta3 / metabolism*
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Transcription, Genetic*

Substances

  • Integrin alpha5
  • Integrin beta3
  • MYC protein, human
  • Protein Subunits
  • Proto-Oncogene Proteins c-myc