Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer

Marisa G. Ponzo, Robert Lesurf, Stephanie Petkiewicz, Frances P. O'Malley, Dushanthi Pinnaduwage, Irene L. Andrulis, Shelley B. Bull, Naila Chughtai, Dongmei Zuo, Margarita Souleimanova, David Germain, Atilla Omeroglu, Robert Cardiff, Michael Hallett, Morag Park

Research output: Contribution to journalArticle

153 Scopus citations

Abstract

Elevated MET receptor tyrosine kinase correlates with poor outcome in breast cancer, yet the reasons for this are poorly understood. We thus generated a transgenic mouse model targeting expression of an oncogenic Met receptor (Metmt) to the mammary epithelium. We show that Metmt induces mammary tumors with multiple phenotypes. These reflect tumor subtypes with gene expression and immunostaining profiles sharing similarities to human basal and luminal breast cancers. Within the basal subtype, Metmt induces tumors with signatures of WNT and epithelial to mesenchymal transition (EMT). Among human breast cancers, MET is primarily elevated in basal and ERBB2-positive subtypes with poor prognosis, and we show that MET, together with EMT marker, SNAIL, are highly predictive of poor prognosis in lymph nodenegative patients. By generating a unique mouse model in which the Met receptor tyrosine kinase is expressed in the mammary epithelium, along with the examination of MET expression in human breast cancer, we have established a specific link between MET and basal breast cancer. This work identifies basal breast cancers and, additionally, poor-outcome breast cancers, as those that may benefit from anti-MET receptor therapies.

Original languageEnglish (US)
Pages (from-to)12903-12908
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number31
DOIs
StatePublished - Aug 4 2009

Keywords

  • Epithelial to mesenchymal transition
  • Gene expression profiling
  • Mouse models

ASJC Scopus subject areas

  • General

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    Ponzo, M. G., Lesurf, R., Petkiewicz, S., O'Malley, F. P., Pinnaduwage, D., Andrulis, I. L., Bull, S. B., Chughtai, N., Zuo, D., Souleimanova, M., Germain, D., Omeroglu, A., Cardiff, R., Hallett, M., & Park, M. (2009). Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 106(31), 12903-12908. https://doi.org/10.1073/pnas.0810402106