Cancer Genetics Group, Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto 4200-465, Portugal.
Oncogene. 2010 Jan 21;29(3):392-402. doi: 10.1038/onc.2009.338. Epub 2009 Nov 9.
Cell-cell adhesion is an elementary process in normal epithelial cellular architecture. Several studies have shown the role mediated by cadherins in this process, besides their role in the maintenance of cell polarity, differentiation and cell growth. However, during tumour progression, these molecules are frequently altered. In breast cancer, tumours that overexpress P-cadherin usually present a high histological grade, show decreased cell polarity and are associated with worse patient survival. However, little is known about how this protein dictates the very aggressive behaviour of these tumours. To achieve this goal, we set up two breast cancer cell models, where P-cadherin expression was differently modulated and analysed in terms of cell invasion, motility and migration. We show that P-cadherin overexpression, in breast cancer cells with wild-type E-cadherin, promotes cell invasion, motility and migration. Moreover, we found that the overexpression of P-cadherin induces the secretion of matrix metalloproteases, specifically MMP-1 and MMP-2, which then lead to P-cadherin ectodomain cleavage. Further, we showed that soluble P-cadherin fragment is able to induce in vitro invasion of breast cancer cells. Overall, our results contribute to elucidate the mechanism underlying the invasive behaviour of P-cadherin expressing breast tumours.
细胞间黏附是正常上皮细胞结构的基本过程。有几项研究表明钙黏蛋白在这个过程中具有中介作用，除了在维持细胞极性、分化和细胞生长方面的作用。然而，在肿瘤进展过程中，这些分子经常发生改变。在乳腺癌中，过度表达 P 钙黏蛋白的肿瘤通常具有较高的组织学分级，表现出细胞极性降低，并与患者生存预后较差相关。然而，关于这种蛋白如何决定这些肿瘤的侵袭性行为，人们知之甚少。为了实现这一目标，我们建立了两种乳腺癌细胞模型，其中 P 钙黏蛋白的表达通过不同的方式进行调节，并从细胞侵袭、运动和迁移的角度进行分析。我们发现，在野生型 E 钙黏蛋白的乳腺癌细胞中过表达 P 钙黏蛋白，可促进细胞侵袭、运动和迁移。此外，我们发现 P 钙黏蛋白的过表达诱导了基质金属蛋白酶（MMPs）的分泌，特别是 MMP-1 和 MMP-2，进而导致 P 钙黏蛋白胞外结构域的裂解。进一步，我们表明可溶性 P 钙黏蛋白片段能够诱导乳腺癌细胞的体外侵袭。总的来说，我们的研究结果有助于阐明 P 钙黏蛋白表达的乳腺癌侵袭性行为的机制。
