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

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

Author information

1
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
2
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
3
Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
4
Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.

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)

PMID:
29774524
PMCID:
PMC6055824
DOI:
10.1002/path.5099
[Indexed for MEDLINE]
Free PMC Article

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