Abstract MIP-072: IDENTIFICATION OF THE SIGNALING PATHWAYS DOWNSTREAM OF PTEN LOSS IN FALLOPIAN TUBE LEADING TO INITIATION AND PROGRESSION OF HGSOC

Abstract

Abstract High-grade serous ovarian carcinoma (HGSOC) is the most common histotype of ovarian cancer with the highest mortality rate. The lethality of these tumors is due mainly to the difficulty in detecting the disease at early stages. The findings of early lesions in the fallopian tube suggest that HGSOC may originate from the fallopian tube epithelium (FTE) and metastasize to the ovary. Recent transgenic animal models of FTE-derived HGSOC have pointed out the critical role of loss of PTEN (phosphatase and tensin homolog) in generating HGSOC when in combination with p53 mutation and alteration of BRCA1/2, but not by itself. Our lab was the first to show that deletion of PTEN alone in FTE is sufficient to lead to tumor formation and peritoneal dissemination suggesting that the importance of PTEN in the early events of the tumorigenic cascade may have been underestimated. Indeed, it has been found that loss of PTEN is a common alteration in STIC lesions. Recent studies revealed that loss of PTEN is predicted to be much more common (30% more) in HGSOC when the DNA contribution from stroma is excluded from tumor DNA analysis. The understanding of the sequence of the molecular alterations behind the genesis of HGSOC from FTE remains poorly defined and pivotal to early detection of HGSOC. The purpose of this study was to identify the markers of cancer initiation and progression altered upon loss of PTEN in FTE. Our data revealed increased mRNA levels of signaling components of the non-canonical (βcatenin-independent) WNT pathway. βcatenin was indeed not activated upon loss of PTEN, however inhibition of the WNT canonical and non-canonical pathway blocked PTEN-induced migration and ovarian colonization suggesting that the WNT non-canonical pathway is mediating loss of PTEN-induced tumorigenesis. Citation Format: Angela Russo, Joanna E. Burdette. IDENTIFICATION OF THE SIGNALING PATHWAYS DOWNSTREAM OF PTEN LOSS IN FALLOPIAN TUBE LEADING TO INITIATION AND PROGRESSION OF HGSOC [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-072.