p130Cas substrate domain signaling promotes migration, invasion, and survival of estrogen receptor-negative breast cancer cells.
p130Cas substrate domain signaling promotes migration, invasion, and survival of estrogen receptor-negative breast cancer cells.
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DOI：
10.2147/bctt.s6255
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Hanks SK
中科院分区：
文献类型：
--
作者：
Cunningham-Edmondson AC;Hanks SK
Src酪氨酸激酶活性升高通常在乳腺癌中观察到，并可能导致肿瘤和恶性肿瘤。p130 Cas（“Crk相关底物”）是在整联蛋白介导细胞粘附至细胞外基质的位点处发现的主要Src底物。Src磷酸化p130 Cas“底物结构域”（SD）中的多个酪氨酸，并且该信号传导事件与促进细胞运动性有关，主要来自对成纤维细胞的研究。在乳腺癌中，对p130 Cas的研究集中在其在赋予表达雌激素受体（ER+）的细胞抗雌激素抗性中的作用。然而，关于p130 Cas在更具侵袭性的雌激素受体阴性（ER-）乳腺癌中的作用知之甚少，需要开发有效的靶向治疗。我们发现高水平的p130 Cas SD酪氨酸磷酸化是ER-乳腺癌细胞系的共同特征，在BT-549细胞系中观察到特别高的水平。使用RNA干扰敲低BT-549细胞中的p130 Cas表达，结合WT p130 Cas相对于信号缺陷对照的拯救，我们提供了证据表明p130 Cas SD酪氨酸磷酸化是该ER-乳腺癌细胞系的迁移、侵袭、增殖和存活中的重要信号事件。
Elevated Src tyrosine kinase activity is commonly observed in breast cancer and likely contributes to neoplasia and malignancy. p130Cas (“Crk-associated substrate”) is a major Src substrate found at the sites where integrins mediate cell adhesion to the extracellular matrix. Src phosphorylates multiple tyrosines in the p130Cas “substrate domain” (SD) and this signaling event has been implicated in the promotion of cell motility, primarily from studies on fibroblasts. In breast cancer, studies on p130Cas have focused on its role in conferring antiestrogen resistance to cells that express the estrogen receptor (ER+). However, little is known regarding the role of p130Cas in the more aggressive estrogen receptor negative (ER−) breast cancers for which there is a need for development of effective targeted therapies. We found high levels of p130Cas SD tyrosine phosphorylation to be a common characteristic of ER− breast cancer cell lines, with particularly high levels observed for the BT-549 cell line. Using RNA interference to knock down p130Cas expression in BT-549 cells, combined with rescue by WT p130Cas versus a signaling-deficient control, we provide evidence that p130Cas SD tyrosine phosphorylation is an important signaling event in the migration, invasion, proliferation, and survival of this ER- breast cancer cell line.