αE-catenin is a candidate tumor suppressor for the development of E-cadherin-expressing lobular-type breast cancer
| Autor: | 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. |
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| Přispěvatelé: | Jonkers, Jos [0000-0002-9264-9792], Derksen, Patrick Wb [0000-0003-0732-7762], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
rho GTP-Binding Proteins
Rho/Rock mouse model lobular breast cancer Breast Neoplasms α-catenin (CTNNA1) Pathology and Forensic Medicine Antigens CD Cell Adhesion Animals Humans Genetic Predisposition to Disease Neoplasm Invasiveness skin and connective tissue diseases Cell Shape Cell Proliferation Mice Knockout rho-Associated Kinases Tumor Suppressor Proteins E-cadherin Actomyosin Adherens Junctions Anoikis Cadherins body regions Gene Expression Regulation Neoplastic Carcinoma Lobular Phenotype Mutation MCF-7 Cells Female Tumor Suppressor Protein p53 alpha Catenin Signal Transduction |
| Zdroj: | Journal of Pathology, 245(4), 456. John Wiley and Sons Ltd |
| ISSN: | 0022-3417 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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