E2F3a Is Critically Involved in Epidermal Growth Factor Receptor–Directed Proliferation in Ovarian Cancer

Abstract We describe for the first time a new integral molecular pathway, linking transcription factor E2F3a to epi-dermal growth factor receptor (EGFR) activation in ovarian cancer cells. Investigations on the role of E2Ffamily members in EGFR-mediated mitogenic signaling revealed that E2F3a was selectively upregulatedfollowing EGFR activation, whereas all other E2F family members remained unaffected. In contrast, EGFtreatment of healthy ovarian surface epithelial and mesothelial cells yielded a selective upregulation ofproliferation-promoting E2F1 and E2F2 without influencing E2F3a expression. In ovarian cancer cell lines,the extent of EGF-induced proliferative stimulus was closely related to the magnitude of E2F3a increase,and proliferation inhibition by E2F3a knockdown was not overcome by EGF exposure. Furthermore, theEGFR-E2F3a axis was found to be signal transducer and activator of transcription 1/3 dependent and theratio of IFN-regulatory factor (IRF)-1 to IRF-2 was shown to be determinative for E2F3a control. In a pilotstudy on 32 primary ovarian cancer specimens, a highly significant correlation between activated EGFR andE2F3a expression was disclosed. This new integral pathway in the EGFR-driven mitogenic cell response, whichthrough its key player E2F3a was found to be essential in triggering proliferation in ovarian cancer cells,provides new insights into EGFR signaling and could represent the basis for appealing new therapeutic ap-proaches in ovarian cancer.