Abstract 993: Identification of estrogen receptor alpha 1 bound lncRNAs in aggressive breast cancer

Abstract Breast cancer (BC) is the second most common newly diagnosed cancer and the second leading cause of cancer death among women in the United States. Around 70% of diagnosed BCs are estrogen receptor positive (ER+). Despite the proven benefits of adjuvant endocrine therapy in women with hormone receptor positive breast cancer, relapses still occur even after initial treatment with endocrine therapy for 5 years, referred to as late stage relapse. While existing studies have focused on the role of protein-coding genes, long non-coding RNAs (lncRNAs) are an emerging and under-characterized class of transcripts that have been shown to be dysregulated in breast cancer. Recently, lncRNAs have been shown to function by interfacing with corresponding RNA binding proteins to play critical regulatory roles in chromatin remodeling and diverse cellular processes by acting as decoys, guides, and scaffolds. As estrogen receptor expression is controlled mostly by epigenetic and post-transcriptional mechanisms, and very rarely at the genomic level, we hypothesize that lncRNAs may interact with ER to promote aggressive disease. To address this, we aimed to identify lncRNAs bound to the estrogen receptor alpha 1 (ESR1) that promote late stage breast cancer. To accomplish this, we first used transcriptome sequencing to identify altered expression levels of lncRNAs between primary tumors and late-stage relapse breast cancer patients. We detected 2086 altered lncRNAs when comparing the metastatic to the primary samples with an FDR <0.05, of which 202 were novel. As expected, Gene Set Enrichment Analysis of differentially expressed protein-coding genes revealed an enrichment of biological concepts associated with breast cancer and metastasis. Next, in order to identify ESR1 bound lncRNAs associated with aggressive disease, we conducted RNA Immunoprecipitation Sequencing (RIP-Seq) of all transcripts bound to ESR1 as compared to an IgG control in the ER+ T47D cell line in triplicate. We identified 210 transcripts bound to ESR1, which we term ESR1 bound lncRNAs (ESRlncs). The identified ESRlncs consisted of both novel (unannotated) and known (annotated) lncRNAs. Interestingly we found ∼50% of ESRlncs had significantly altered expression in the metastatic samples, with 96% (105) having more than a two fold increase in expression. Further characterization of these ESRlncs is ongoing to decipher how they interact with ESR1 to promote aggressive and metastatic disease. Overall, this is the first study to discover ESR1 bound lncRNAs that may be contributing to late stage relapse in breast cancer patients. Citation Format: Jessica M. Silva-Fisher, Abdallah M. Eteleeb, Torsten O. Nielsen, Charles M. Perou, Jorge S. Reis-Filho, Mathew J. Ellis, Elaine R. Mardis, Christopher A. Maher. Identification of estrogen receptor alpha 1 bound lncRNAs in aggressive breast cancer. [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 993.

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