Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer

Jennifer F. Knight, Robert Lesurf, Hong Zhao, Dushanthi Pinnaduwage, Ryan R. Davis, Sadiq M I Saleh, Dongmei Zuo, Monica A. Naujokas, Naila Chughtai, Jason I. Herschkowitz, Aleix Prat, Anna Marie Mulligan, William J. Muller, Robert Cardiff, Jeffrey Gregg, Irene L. Andrulis, Michael T. Hallett, Morag Park

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50 Scopus citations

Abstract

Triple-negative breast cancer (TNBC) accounts for ∼20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Metmt) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Metmt mice with conditional loss of murine p53 (Trp53) in mammary epithelia. Somatic Trp53 loss, in combination with Metmt, significantly increased tumor penetrance over Metmt or Trp53 loss alone. Unlike Metmt tumors, which are histologically diverse and enriched in a basal-like molecular signature, the majority of Metmt tumors with Trp53 loss displayed a spindloid pathology with a distinct molecular signature that resembles the human claudin-low subtype of TNBC, including diminished claudins, an epithelial-tomesenchymal transition signature, and decreased expression of the microRNA-200 family. Moreover, although mammary specific loss of Trp53 promotes tumors with diverse pathologies, those with spindloid pathology and claudin-low signature display genomic Met amplification. In both models, MET activity is required for maintenance of the claudin-lowmorphological phenotype, in which MET inhibitors restore cell-cell junctions, rescue claudin 1 expression, and abrogate growth and dissemination of cells in vivo. Among human breast cancers, elevated levels of MET and stabilized TP53, indicative of mutation, correlate with highly proliferative TNBCs of poor outcome. This work shows synergy between MET and TP53 loss for claudin-low breast cancer, identifies a restricted claudin-low gene signature, and provides a rationale for anti-MET therapies in TNBC.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number14
DOIs
StatePublished - Apr 2 2013

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Keywords

  • EMT
  • Gene expression
  • Met RTK
  • Mouse model

ASJC Scopus subject areas

  • General

Cite this

Knight, J. F., Lesurf, R., Zhao, H., Pinnaduwage, D., Davis, R. R., Saleh, S. M. I., Zuo, D., Naujokas, M. A., Chughtai, N., Herschkowitz, J. I., Prat, A., Mulligan, A. M., Muller, W. J., Cardiff, R., Gregg, J., Andrulis, I. L., Hallett, M. T., & Park, M. (2013). Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 110(14). https://doi.org/10.1073/pnas.1210353110