Abstract LB-130: STAT3/PIAS3 as “early signature” gene pathways in the development of ovarian high grade serous carcinoma from the fallopian tube

Abstract

Abstract Objectives: Our recent studies in human samples have demonstrated constitutive activation of STAT3 Tyr705 and loss of protein inhibitor of activated STAT3 (PIAS3) in STICs in the fallopian tubes and advanced HGSC tissues. The goal of this current study is to identify and elucidate the molecular mechanisms leading to the initiation and development of HGSC through STAT3 activation and low levels or absence of PIAS3 in the fallopian tube (FT). Methods: Human tissues–benign normal FTs, STICs (without ovarian cancer) and HGSC—were evaluated for expression of STAT3/PIAS3 (as compared with their known TP53 signature) and their target proliferation genes. Isolated primary fallopian tubal serous epithelial carcinoma (FTSEC) cells from FT and immortalized FT cells were also utilized and were evaluated with real time PCR, IHC, ICC, western blots, cloning and orthotopic mouse models. Results: We observed high-level expression of pSTAT3 Tyr705, and decreased levels of PIAS3, in dysplastic areas of FT obtained from patients with and without cancer and advanced stage HGSC (as compared to high PIAS3 low pSTAT3 expression in normal benign FT). In addition, FT cells transfected with a STAT3 overexpression construct showed translocation of pSTAT3 and c-Myc into the nucleus. Further, the in vivo experiments demonstrated that the overexpression of STAT3 in FTSECs promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. In contrast, STAT3 knockdown in ovarian cancer cells was associated with reduced tumor growth and metastasis in vivo. Conclusions: The STAT3 pathway may play a critical role in the development of STIC lesions and their progression to HGSC. We will further screen more FT samples and number of human tissues from various stages of HGSC along with an in vivo mouse model of HGSC in order to establish the oncogenic role of STAT3 and expression levels of PIAS3 in ovarian HGSC. Our current and future findings offer an opportunity to address the clinically important questions that are critical for cancer prevention and early detection in deadly HGSC. Citation Format: Uksha Saini, John Wallbillich, Maria Riley Riley, John M. Fowler, Ross Wanner, Jenny Lester, Beth Karlan, Paul Goodfellow, Adrian Suarez, David Cohn, Karuppaiyah Selvendiran. STAT3/PIAS3 as “early signature” gene pathways in the development of ovarian high grade serous carcinoma from the fallopian tube. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-130.