Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany.
PLoS One. 2013 Aug 30;8(8):e73062. doi: 10.1371/journal.pone.0073062. eCollection 2013.
Inactivation of CDH1, encoding E-cadherin, promotes cancer initiation and progression. According to a newly proposed molecular mechanism, loss of E-cadherin triggers an upregulation of the anti-apoptotic oncoprotein BCL2. Conversely, reconstitution of E-cadherin counteracts overexpression of BCL2. This reciprocal regulation is thought to be critical for early tumor development. We determined the relevance of this new concept in human infiltrating lobular breast cancer (ILBC), the prime tumor entity associated with CDH1 inactivation. BCL2 expression was examined in human ILBC cell lines (IPH-926, MDA-MB-134, SUM-44) harboring deleterious CDH1 mutations. To test for an intact regulatory axis between E-cadherin and BCL2, wild-type E-cadherin was reconstituted in ILBC cells by ectopic expression. Moreover, BCL2 and E-cadherin were evaluated in primary invasive breast cancers and in synchronous lobular carcinomas in situ (LCIS). MDA-MB-134 and IPH-926 showed little or no BCL2 expression, while SUM-44 ILBC cells were BCL2-positive. Reconstitution of E-cadherin failed to impact on BCL2 expression in all cell lines tested. Primary ILBCs were almost uniformly E-cadherin-negative (97%) and were frequently BCL2-negative (46%). When compared with an appropriate control group, ILBCs showed a trend towards an increased frequency of BCL2-negative cases (P = 0.064). In terminal duct-lobular units affected by LCIS, the E-cadherin-negative neoplastic component showed a similar or a reduced BCL2-immunoreactivity, when compared with the adjacent epithelium. In conclusion, upregulation of BCL2 is not involved in lobular breast carcinogenesis and is unlikely to represent an important determinant of tumor development driven by CDH1 inactivation.
CDH1 编码 E-钙黏蛋白的失活促进了癌症的起始和进展。根据一个新提出的分子机制，E-钙黏蛋白的丢失触发了抗凋亡癌蛋白 BCL2 的上调。相反，E-钙黏蛋白的重建抵消了 BCL2 的过表达。这种相互调节被认为对早期肿瘤发展至关重要。我们确定了这一新概念在人浸润性小叶乳腺癌（ILBC）中的相关性，ILBC 是人浸润性小叶乳腺癌的主要肿瘤实体，与 CDH1 失活有关。在携带有害 CDH1 突变的人 ILBC 细胞系（IPH-926、MDA-MB-134、SUM-44）中检查了 BCL2 的表达。为了测试 E-钙黏蛋白和 BCL2 之间的完整调节轴，通过异位表达在 ILBC 细胞中重建野生型 E-钙黏蛋白。此外，还在原发性浸润性乳腺癌和同步小叶原位癌（LCIS）中评估了 BCL2 和 E-钙黏蛋白。MDA-MB-134 和 IPH-926 显示很少或没有 BCL2 表达，而 SUM-44 ILBC 细胞则为 BCL2 阳性。在所有测试的细胞系中，E-钙黏蛋白的重建都未能影响 BCL2 的表达。原发性 ILBC 几乎普遍（97%）E-钙黏蛋白阴性，并且经常 BCL2 阴性（46%）。与适当的对照组相比，ILBC 显示出 BCL2 阴性病例频率增加的趋势（P=0.064）。在受 LCIS 影响的终末导管小叶单位中，与相邻上皮相比，E-钙黏蛋白阴性的肿瘤成分显示出相似或降低的 BCL2 免疫反应性。总之，BCL2 的上调不参与小叶乳腺癌的发生，不太可能成为 CDH1 失活驱动的肿瘤发展的重要决定因素。
