Abstract B23: The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer

Abstract Objectives: To investigate changes in estrogen receptor–alpha (ERα) signaling during the progression of endometriosis to endometriosis-associated ovarian cancer (EAOC) as a putative driver of malignant transformation. Methods: We procured tissue samples of normal endometrium (n=23), endometriosis (benign, n=19; atypical, n=11; concurrent with EAOC, n=9), and EAOC (n=21). In this cohort, we evaluated expression of a 236-gene signature of estrogen signaling. ANOVA and unsupervised clustering were used to identify distinct gene expression profiles across disease states. These profiles were compared to public profiles of estrogen regulation in preclinical cancer models from the Gene Expression Omnibus (GEO). Gene set enrichment analysis (GSEA) was performed to determine whether gene expression in EAOC was consistent with ERα activity. Results: ANOVA revealed 158 differentially expressed genes (q<0.05) and unsupervised clustering identified 4 distinct gene clusters. Cluster 1 comprises genes with increasing expression from benign endometriosis to EAOC (e.g. FGF18, ESR2). Clusters 2 and 3 include genes that are overexpressed or downregulated in EAOC compared to benign endometriosis, respectively (e.g., NRIP1, IGFBP3). Cluster 4 consists of genes with an incremental decrease in expression from benign endometriosis to EAOC (e.g., ESR1, PGR, and GREB1). The estrogen signaling profile of EAOC was not consistent with activated ERα in the preclinical models. Further, GSEA did not identify signatures of activated ERα in EAOC but instead identified expression patterns consistent with loss of ERα function and development of endocrine resistance. Conclusions: Gene expression data suggest that classical ERα signaling becomes inactivated throughout the progression of endometriosis to EAOC. Rather, the gene expression pattern in EAOC is more consistent with profiles of endocrine resistance. De-repression of ERα target genes such as FGF18 may contribute to evolution of endometriosis into EAOC. Citation Format: Michelle Boisen, Courtney Andersen, Matt Sikora, Tianzhou Ma, George Tseng, Anda Vlad, Esther Elishaev, Uma Chandran, Robert Edwards, Steffi Oesterreich. The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B23.