Abstract LB-B15: New causal drivers of estrogen signaling revealed by dense time series of nascent RNA transcription

Abstract

Abstract Mechanistic understanding of Estrogen Receptor (ER) signaling will lead to new therapeutic targets for ER positive breast cancer. To this end, Arpeggio performed nascent RNA sequencing following estradiol (E2) treatment in MCF7 breast cancer cells every 15 minutes for 6 hours. To date, our study represents the densest time series of estrogen signaling ever reported. Arpeggio noted three transcriptional waves following E2 treatment: peaks at 30 minutes, 2.5 hours and 5 hours respectively. We noted that the early response was enriched for canonical ER signaling, however mid and late response were enriched for metabolic processes. Because our study was statistically powered with 24 time points, we could use delay-coordinate embedding to look for causal gene interactions. We implicated NME2 as the causal driver of the 5-hour transcriptional wave. Indeed, NME2 and Estrogen Receptor (ER) have been shown to co-localize where NME2 blocks ER effect. Our study represents a new methodology for target discovery in hormone driven cancers. Citation Format: Ryan Langendorf, Joel Basken, Maria Lai, Joseph Azofeifa. New causal drivers of estrogen signaling revealed by dense time series of nascent RNA transcription [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B15. doi:10.1158/1535-7163.TARG-19-LB-B15