αE-catenin is a candidate tumor suppressor for the development of E-cadherin-expressing lobular-type breast cancer
de Groot, Jolien S.; Ratze, Max A.K.; van Amersfoort, Miranda; Eisemann, Tanja; Vlug, Eva J.; Niklaas, Mijanou T.; Chin, Suet Feung; Caldas, Carlos; van Diest, Paul J.; Jonkers, Jos; de Rooij, Johan; Derksen, Patrick W.B.
(2018) Journal of Pathology, volume 245, issue 4, pp. 456 - 467
(Article)
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,
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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.
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Keywords: E-cadherin, lobular breast cancer, mouse model, Rho/Rock, α-catenin (CTNNA1), alpha Catenin/genetics, Cell Proliferation, Humans, Gene Expression Regulation, Neoplastic, Carcinoma, Lobular/genetics, MCF-7 Cells, Cell Shape, Female, Genetic Predisposition to Disease, Signal Transduction, Neoplasm Invasiveness, Antigens, CD/genetics, Actomyosin/metabolism, rho-Associated Kinases/metabolism, Cell Adhesion, Adherens Junctions/genetics, Mice, Knockout, Cadherins/genetics, Tumor Suppressor Proteins/genetics, Phenotype, Animals, rho GTP-Binding Proteins/metabolism, Anoikis, Breast Neoplasms/genetics, Mutation, Tumor Suppressor Protein p53/deficiency, alpha-catenin (CTNNA1), Pathology and Forensic Medicine, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0022-3417
Publisher: John Wiley & Sons Inc.
Note: Funding Information: Special thanks go to the UMC Utrecht Cell Microscopy Center (CMC) for providing microscopy assistance. All members of the Derksen, Van Diest, Jonkers, and De Rooij laboratories are acknowledged for support and discussions. We are indebted to The Netherlands Cancer Institute mouse facility for support during the longitudinal tumor studies. This work was supported by a grant from The Netherlands Organization for Scientific Research (NWO-VIDI 917.96.318), Foundation Vrienden UMC Utrecht (11.081), Dutch Cancer Society grants (KWF-UU-2011-5230, KWF-UU-2014-7201 and KWF-2017-10456), and the European Union's Horizon 2020 FET Proactive programme under the grant agreement No. 731957 (MECHANO-CONTROL). Funding Information: Special thanks go to the UMC Utrecht Cell Microscopy Center (CMC) for providing microscopy assistance. All members of the Derksen, Van Diest, Jonkers, and De Rooij laboratories are acknowledged for support and discussions. We are indebted to The Netherlands Cancer Institute mouse facility for support during the longitudinal tumor studies. This work was supported by a grant from The Netherlands Organization for Scientific Research (NWO-VIDI 917.96.318), Foundation Vrienden UMC Utrecht (11.081), Dutch Cancer Society grants (KWF-UU-2011-5230, KWF-UU-2014-7201 and KWF-2017-10456), and the European Union’s Horizon 2020 FET Proactive programme under the grant agreement No. 731957 (MECHANO-CONTROL). Publisher Copyright: © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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