Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
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.
J Pathol. 2018 Aug;245(4):456-467. doi: 10.1002/path.5099. Epub 2018 Jun 20.
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.
虽然 E-钙黏蛋白（CDH1）的突变失活是浸润性小叶乳腺癌（ILC）的主要驱动因素，但在存在明显非黏附性和浸润性小叶生长模式的情况下，约有 10-15%的所有 ILC 仍保留膜定位的 E-钙黏蛋白。鉴于 ILC 依赖于组成型肌动球蛋白收缩来促进肿瘤的发展和进展，我们使用了一系列细胞系统和体内实验来研究α-连环蛋白（CTNNA1）缺失对非浸润性乳腺癌的锚定独立性的调控后果。我们发现，人类乳腺癌中失活的体细胞 CTNNA1 突变与小叶和混合导管小叶表型相关。此外，在小鼠和人 E-钙黏蛋白表达的乳腺癌细胞中诱导性缺失α-连环蛋白导致 E-钙黏蛋白的非典型定位、圆形细胞形态和抗失巢凋亡。随后的药理抑制实验表明，与 E-钙黏蛋白突变型 ILC 相似，α-连环蛋白缺失诱导的抗失巢凋亡依赖于 Rho/Rock 依赖性肌动球蛋白收缩性。最后，使用基于移植的条件性小鼠模型，我们证明了诱导性α-连环蛋白失活引发小叶特征和侵袭行为的获得。因此，我们认为α-连环蛋白是小叶型乳腺癌发展的真正肿瘤抑制因子，因此提供了与 E-钙黏蛋白失活、黏附连接（AJ）功能障碍和随后的组成型肌动球蛋白收缩不同的替代事件。
