αE-catenin is a candidate tumor suppressor for the development of E-cadherin-expressing lobular-type breast cancer

J Pathol. 2018 Aug;245(4):456-467. doi: 10.1002/path.5099. Epub 2018 Jun 20.

Abstract

Although mutational inactivation of E-cadherin (CDH1) is the main driver of invasive lobular breast cancer (ILC), approximately 10-15% of all ILCs retain membrane-localized E-cadherin despite the presence of an apparent non-cohesive and invasive lobular growth pattern. Given that ILC is dependent on constitutive actomyosin contraction for tumor development and progression, we used a combination of cell systems and in vivo experiments to investigate the consequences of α-catenin (CTNNA1) loss in the regulation of anchorage independence of non-invasive breast carcinoma. We found that inactivating somatic CTNNA1 mutations in human breast cancer correlated with lobular and mixed ducto-lobular phenotypes. Further, inducible loss of α-catenin in mouse and human E-cadherin-expressing breast cancer cells led to atypical localization of E-cadherin, a rounded cell morphology, and anoikis resistance. Pharmacological inhibition experiments subsequently revealed that, similar to E-cadherin-mutant ILC, anoikis resistance induced by α-catenin loss was dependent on Rho/Rock-dependent actomyosin contractility. Finally, using a transplantation-based conditional mouse model, we demonstrate that inducible inactivation of α-catenin instigates acquisition of lobular features and invasive behavior. We therefore suggest that α-catenin represents a bona fide tumor suppressor for the development of lobular-type breast cancer and as such provides an alternative event to E-cadherin inactivation, adherens junction (AJ) dysfunction, and subsequent constitutive actomyosin contraction. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Keywords: E-cadherin; Rho/Rock; lobular breast cancer; mouse model; α-catenin (CTNNA1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actomyosin / metabolism
  • Adherens Junctions / genetics
  • Adherens Junctions / metabolism
  • Adherens Junctions / pathology
  • Animals
  • Anoikis
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Carcinoma, Lobular / genetics
  • Carcinoma, Lobular / metabolism*
  • Carcinoma, Lobular / pathology
  • Cell Adhesion*
  • Cell Proliferation
  • Cell Shape
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • MCF-7 Cells
  • Mice, Knockout
  • Mutation
  • Neoplasm Invasiveness
  • Phenotype
  • Signal Transduction
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • alpha Catenin / genetics
  • alpha Catenin / metabolism*
  • rho GTP-Binding Proteins / metabolism
  • rho-Associated Kinases / metabolism

Substances

  • Antigens, CD
  • CDH1 protein, human
  • CTNNA1 protein, human
  • Cadherins
  • Cdh1 protein, mouse
  • Ctnna1 protein, mouse
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • alpha Catenin
  • Actomyosin
  • rho-Associated Kinases
  • rho GTP-Binding Proteins