Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells.
Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells.
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DOI：
10.1158/0008-5472.can-08-1694
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Bissell MJ
中科院分区：
文献类型：
--
作者：
Fournier MV;Fata JE;Martin KJ;Yaswen P;Bissell MJ
PTEN 是一种双功能磷酸酶，其肿瘤抑制功能在多种癌症中均受到损害。由于组织极性和结构是正常和恶性行为的关键调节因子，因此我们推测 PTEN 可能在维持组织完整性方面发挥作用。我们使用了两种非恶性人乳腺上皮细胞系 (HMEC)，它们在富含层粘连蛋白的 3 维细胞外基质凝胶 (3D lrECM) 中培养时形成极化的生长停滞结构 (腺泡)。当腺泡开始形成时，PTEN 在细胞质和细胞与细胞接触处积累，并与 E-钙粘蛋白/β-连环蛋白复合物共定位。 lrECM 中 shRNA 降低 PTEN 水平可防止有组织的乳腺腺泡的形成并破坏生长停滞。重要的是，E-钙粘蛋白功能阻断抗体破坏腺泡极性和细胞间接触会降低内源性 PTEN 蛋白水平并抑制其在细胞间接触处的积累。相反，在缺乏内源性E-钙粘蛋白表达的SKBR3乳腺癌细胞中，外源性引入E-钙粘蛋白基因会诱导PTEN表达及其在细胞相互作用位点的积累。这些研究提供的证据表明，E-钙粘蛋白调节 PTEN 蛋白水平及其在 3D lrECM 中向细胞-细胞连接处的募集，表明结构完整性与 PTEN 水平和定位之间的动态相互作用。因此，这种相互作用似乎是乳腺上皮细胞增殖和形态发生信号传导的关键整合者。
PTEN is a dual function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two non-malignant human mammary epithelial cell lines (HMECs) that form polarized, growth-arrested structures (acini) when cultured in 3-dimensional laminin-rich extracellular matrix gels (3D lrECM). As acini begin to form, PTEN accumulates in both the cytoplasm, and at cell-cell contacts where it co-localizes with E-cadherin/β-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in SKBR3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in 3D lrECM indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus appears to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells.