| First Author | de Groot JS | Year | 2018 |
| Journal | J Pathol | Volume | 245 |
| Issue | 4 | Pages | 456-467 |
| PubMed ID | 29774524 | Mgi Jnum | J:265844 |
| Mgi Id | MGI:6199755 | Doi | 10.1002/path.5099 |
| Citation | de Groot JS, et al. (2018) alphaE-catenin is a candidate tumor suppressor for the development of E-cadherin-expressing lobular-type breast cancer. J Pathol 245(4):456-467 |
| abstractText | 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 alpha-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 alpha-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 alpha-catenin loss was dependent on Rho/Rock-dependent actomyosin contractility. Finally, using a transplantation-based conditional mouse model, we demonstrate that inducible inactivation of alpha-catenin instigates acquisition of lobular features and invasive behavior. We therefore suggest that alpha-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. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
