Ligand-independent activation of estrogen receptor pathway in gynecologic malignancies

(1)PAK 1是小GTP酶、生长因子和脂质信号传导的主要靶点，调节细胞运动性、激素作用、侵袭性和存活，所有这些都是肿瘤发展所必需的。我们通过免疫组化染色发现14%的卵巢癌患者磷酸化PAK 1表达。肿瘤中磷酸化PAK 1（+）表达的患者与阴性表达的患者相比生存率低（P=0.02）。此外，PAK 1特异性抑制剂（PAK 18）抑制PAK 1大大增加了磷酸化PAK 1阳性卵巢癌细胞对表阿霉素的敏感性。(2)在早期卵巢癌患者中，与Vav 1阴性肿瘤相比，Vav 1阳性肿瘤的总生存期（P=0.0392）和无进展生存期（P=0.0298）更差。与对照细胞相比，在SKOV-3-Vav 1中观察到E-钙粘蛋白的显著下调。VAV 1的表达通过抑制E-cadherin而促进上皮-间质转化和卵巢癌的进展。

(1) PAK1, a major target of the small GTPases, growth factors and lipid signaling, regulates cell motility, hormone action, invasiveness, and survival, all of which are required for tumor development. We found phospho-PAK1 expression in 14% by immunohistochemical staining of ovarian cancer patients. Patients with phospho-PAK1 (+) in the tumor had poor survival compared with those with negative expression (P=0.02). Furthermore, PAK1 inhibition by PAK1 specific inhibitor (PAK18) greatly increased the sensitivity of phospho-PAK1 positive ovarian cancer cells to epirubicin.(2) Vav1-positive tumors had a worse overall survival (P=0.0392) and progression free survival (P=0.0298) compared to Vav1-negative tumors in early-stage ovarian cancer patients. Significant down-regulation of E-cadherin was observed in SKOV-3-Vav1 versus control cells. Expression of VAV1 causally contributes to epithelial-mesenchymal transition and ovarian cancer progression through the suppression of E-cadherin.