A functional analysis of nuclear RhoGEF Ect2 in ovarian cancer (2012)
Undergraduates: Molly DeCristo, Lauren E. Parker Dimitri Trembath, Pei-Fen Kuan, Adrienne D. Cox, Channing J. Der, et al.
Faculty Advisor: Adrienne Cox
Department: Biology
Ect2 is a guanine nucleotide exchange factor (GEF) and activator of Rho family small GTPases. Ect2 regulates RhoA, Rac1, and Cdc42, thereby playing a role in the control of cell proliferation, survival, and migration. Originally identified as an oncogene in vitro, the role of Ect2 in regulating migration makes it of particular interest in ovarian cancer, in which local invasion and ascites are prevalent. Notably, ECT2 is located on 3q26.1-3q26.2, the most frequent amplicon in ovarian cancer. We first explored the role of Ect2 in ovarian cancer by knocking it down using shRNA and assessing anchorage-independent growth and random and directed migration in a panel of ovarian cancer cell lines. Our findings reveal that Ect2 expression is required for each of these functions. In addition, we studied the expression and localization of Ect2 in primary epithelial ovarian cancers, using over 300 histological tumor and cyst samples incorporated into a tissue microarray. Ect2 is unusual among the RhoGEFs because of its localization. A critical regulator of cytokinesis, it is sequestered to the nucleus in interphase cells. It has been hypothesized that the overexpression and mislocalization of Ect2 into the cytoplasm leads to aberrant Rho activation and oncogenesis. Unexpectedly, our recently completed TMA data analysis suggests that malignant serous ovarian cancer is instead associated with nuclear Ect2. We are currently exploring a possible nuclear mechanism to explain these findings.