P-cadherin role in normal breast development and cancer
P-cadherin role in normal breast development and cancer
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DOI：
10.1387/ijdb.113382aa
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发表时间：
2011-01-01
影响因子：
0.7
通讯作者：
Paredes, Joana
中科院分区：
文献类型：
--
作者：
Albergaria, Andre;Ribeiro, Ana-Sofia;Paredes, Joana
P-cadherin是一种细胞间黏附分子，其表达与正常成人上皮组织中未分化细胞以及低分化癌高度相关。它在人类胚胎干细胞中的表达已被报道，并被认为是一些上皮组织的干细胞或祖细胞的标记物。在正常乳腺中，p -钙粘蛋白在乳腺导管分支过程中起重要作用，它通过终芽上皮帽细胞单层表达。在成熟乳腺组织中，其表达仅限于肌上皮；据推测，它也可能存在于早期腔内祖细胞中。在乳腺癌中，p -钙粘蛋白经常在高级别肿瘤中过度表达，是一个公认的患者预后不良的指标。据报道，它是癌细胞迁移和侵袭的重要诱导剂，其潜在的分子机制包括其近膜结构域介导的信号传导，基质金属蛋白酶向细胞外介质的分泌，以及具有促侵袭活性的p -钙粘蛋白可溶性形式的裂解。在细胞内，该蛋白干扰内源性钙粘蛋白/连环蛋白复合物，诱导p120-连环蛋白向细胞质脱位，随后激活Rac1/Cdc42，并导致肌动蛋白细胞骨架的相关改变。考虑到P-cadherin在癌细胞侵袭和转移形成中的作用，最近产生了一种人源化单克隆抗体来拮抗P-cadherin相关的信号通路，目前正在进行I期临床试验。在这篇综述中，关于p -钙粘蛋白在正常乳腺发育和癌症中的作用的最重要的发现将被说明和讨论，重点是最新的数据。
P-cadherin is a cell-cell adhesion molecule, whose expression is highly associated with undifferentiated cells in normal adult epithelial tissues, as well as with poorly differentiated carcinomas. Its expression has been already reported in human embryonic stem cells and it is presumed to be a marker of stem or progenitor cells of some epithelial tissues. In normal breast, P-cadherin has an essential role during ductal mammary branching, being expressed by the monolayer of epithelial cap cells at the end buds. In mature mammary tissue, its expression is restricted to the myoepithelium; it has been postulated that it may also be present in early luminal progenitor cells. In breast cancer, P-cadherin is frequently overexpressed in high-grade tumours, being a well-established indicator of poor patient prognosis. It has been reported as an important inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloproteases to the extracellular media, and the cleavage of a P-cadherin soluble form with pro-invasive activity. Intracellularly, this protein interferes with the endogenous cadherin/catenin complex, inducing p120-catenin delocalization to the cytoplasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton. Considering P-cadherin's role in cancer cell invasion and metastasis formation, a humanized monoclonal antibody was recently produced to antagonize P-cadherin-associated signalling pathways, which is currently under Phase I clinical trials. In this review, the most important findings about the role of P-cadherin in normal breast development and cancer will be illustrated and discussed, with emphasis on the most recent data.