Loss of p120-catenin induces metastatic progression of breast cancer by inducing anoikis resistance and augmenting growth factor receptor signaling

Cancer Res. 2013 Aug 1;73(15):4937-49. doi: 10.1158/0008-5472.CAN-13-0180. Epub 2013 Jun 3.

Abstract

Metastatic breast cancer remains the chief cause of cancer-related death among women in the Western world. Although loss of cell-cell adhesion is key to breast cancer progression, little is known about the underlying mechanisms that drive tumor invasion and metastasis. Here, we show that somatic loss of p120-catenin (p120) in a conditional mouse model of noninvasive mammary carcinoma results in formation of stromal-dense tumors that resemble human metaplastic breast cancer and metastasize to lungs and lymph nodes. Loss of p120 in anchorage-dependent breast cancer cell lines strongly promoted anoikis resistance through hypersensitization of growth factor receptor (GFR) signaling. Interestingly, p120 deletion also induced secretion of inflammatory cytokines, a feature that likely underlies the formation of the prometastatic microenvironment in p120-negative mammary carcinomas. Our results establish a preclinical platform to develop tailored intervention regimens that target GFR signals to treat p120-negative metastatic breast cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoikis / physiology*
  • Blotting, Western
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Catenins / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Neoplasm Invasiveness / pathology
  • Receptors, Growth Factor / metabolism*
  • Signal Transduction / physiology*

Substances

  • Catenins
  • Receptors, Growth Factor
  • delta catenin