Abstract GMM-045: PAX8 PLAYS AN ESSENTIAL ROLE IN HIGH GRADE SEROUS OVARIAN CANCER VIA ACTIVATION OF MUTANT P53 AND MISLOCALIZED P21

Abstract

Abstract High grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer, and a very deadly disease, mostly due to lack of early detection methods. Wide spread disease at diagnosis has delayed the understanding that it often originates from the fallopian tube. This novel understanding has led to increased interest in fallopian tube developmental lineage markers, such as PAX8. In the adult fallopian tube, PAX8 is expressed in the fallopian tube secretory epithelial cell (FTSEC) and its expression is maintained through the process of FTSEC transformation Serous Tubal Intraepithelial Carcinoma (STIC) and to HGSC. We show that PAX8 has an essential pro-proliferative and anti-apoptotic role in HGSC. This role is mediated through direct transcriptional activation of mutated TP53, which often carries missense mutations that potentially lead to gain of function (GOF) oncogenic activities. Surprisingly, mutant p53 binds the p21 promoter and transcriptionally activates the expression of p21, which localizes to the cytoplasm of cells where it plays a non-canonical, pro-proliferative role. While in normal fallopian tube p21 is nuclear as expected, and STIC shows a mix of nuclear and cytoplasmic staining, an analysis of p21 staining in EOC shows that cytoplasmic p21 expression correlates with bad prognostic factors. Together, our findings illustrate that in HGSC TP53 mutations and abnormal p21 localization subvert a normal developmental pathway into a driver of tumor progression. Citation Format: Dima Ghannam, Eyal Jacob, Reli Kakun, Tanya Wasserman, Lina Korsensky, Ofir Sternfeld, Julia Kagan, Debora Rosa Bublik, Sarit Aviel-Ronen, Keren Levanon, Edmond Sabo, Sarit Larisch, Moshe Oren, Dov Hershkovitz, Ruth Perets. PAX8 PLAYS AN ESSENTIAL ROLE IN HIGH GRADE SEROUS OVARIAN CANCER VIA ACTIVATION OF MUTANT P53 AND MISLOCALIZED P21 [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-045.