Ovarian cancer is often diagnosed at a late stage, when cancer cells have already migrated and invaded other tissues and organs. Wang and colleagues from the University of Colorado Denver and the Dana-Farber Cancer Institute in Boston, showed that Gab2—a scaffolding adaptor protein that is overexpressed in a subset of ovarian tumors and in other cancers—can act to increase migration and invasion and turn on the epithelial-to-mesenchymal program through activation of the PI3K-Zeb1 pathway in ovarian cancer.
These investigators showed that overexpression of Gab2 in ovarian cancer cells with normally low Gab2 expression resulted in increased cell migration and invasion and downregulation of expression of E-cadherin, an epithelial cell marker involved in cell-cell contact. Knockdown of Gab2 expression in cells with high Gab2 expression inhibited migration and invasion and upregulated E-cadherin expression.
Studies of wild-type Gab2 and mutants defective in activation of the PI3K and Shp2-Erk pathways showed that Gab2 inhibited E-cadherin expression and increased the expression of Zeb1—a transcription factor involved in epithelial-to-mesenchymal transition (EMT) and cell migration and invasion—through the activation of the PI3K pathway. Knockdown of Zeb1 blocked Gab2-induced downregulation of E-cadherin expression and increased cell invasion. PI3K inhibitors and rapamycin (an inhibitor of the PI3K downstream target mTOR) acted to reverse the effects of Gab2 on migration and invasion.
As stated by the investigators, “Our finding reveals that Gab2 overexpression contributes to activation of the PI3K pathway and promotes EMT in a subset of ovarian cancer…. Considering [that PI3K inhibitors] or rapamycin can reduce Gab2-enhanced cell migration and invasion of ovarian cancer cells, drugs that target the PI3K/mTOR pathway can be potentially used to treat Gab2-overexpressed ovarian cancer in combination with standard chemotherapy.” ■
Wang Y, et al: Oncogene 31:2512–2520, 2012.