Ligand-independent activation of estrogen receptor pathway in gynecologic malignancies

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(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.