Abstract 1044: Role of autophagic mediators in the transition from endometriosis to endometriosis-associated ovarian cancers

Abstract Endometriosis, a common painful and inflammatory gynecological disease, has been proposed to contribute to the development of endometriosis-associated ovarian cancer, specifically the endometrioid and clear cell subtypes. The mechanism underlying this transition is unclear; however, many characteristics of endometriosis and endometrioid-ovarian cancer are similar with the exception of loss of cell cycle control. Autophagy, a survival mechanism which is activated in response to multiple stresses promotes tumorigenic development and may be an ideal target for therapy. To date, the role of autophagy in the development of endometrioid-ovarian carcinomas is unknown with the exception of attenuated mRNA levels of the autophagic marker, beclin-1, in an endometriosis-related condition. Since we have shown that SnoN/SkiL, a TGFβ co-transcriptional regulator, modulates autophagy in ovarian cancer cell lines, we propose that SnoN and/or autophagic mediators may be involved in the transition from endometriosis to ovarian cancer. Thus, we determined the basal expression levels of markers of TGFβ and autophagic pathways in primary and SV40 LTg immortalized endometriotic cells isolated from patients with endometriosis and compared their levels to endometrial/ovarian carcinoma cell lines. Cell lysates were prepared from confluent cultures of (1) five endometrial carcinoma cell lines (MFE296, MFE319, AN3-CA, KLE, and HEC-1A), (2) endometrioid-ovarian carcinoma cell line (TOV112D), (3) a clear cell carcinoma cell line (TOV21G), (4) three serous epithelial ovarian carcinoma cell lines (OVCAR8, HEY, and SKOV3), and (5) two primary (PNEs) as well as four SV40 LTg immortalized (INEs) normal endometriotic cells (derived from patients with endometriotic lesions). These were then assessed for protein expression levels of markers in various signaling pathways (autophagy, TGFβ, cell survival, and epithelial-mesenchymal transition) via western analysis and densitometric analysis. Relative to endometrial/serous epithelial ovarian carcinomas, PNEs and INEs expressed (1) low levels of oncogenes (EVI1, SnoN, and EGFR), (2) elevated levels of tumor suppressors (PTEN), (3) elevated levels of the EMT marker N-Cadherin, and (4) low levels of autophagic markers (i.e. ATG5, ATG7, and hVps34). Since we have observed marked differences in expression of autophagy and TGFβ signaling mediators, studies are ongoing to investigate the effects of knockdown and overexpression of ATGs and SnoN/SkiL in TOV112D and INEs, respectively, to determine their role in modulating this transition event. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1044. doi:10.1158/1538-7445.AM2011-1044