Abstract P2-04-03: Epigenomic analysis of cancer stem cell (CSC)-enriched triple-negative breast cancer (TNBC) populations reveals gene regulatory circuitry and novel tumor cell vulnerabilities

Abstract Tumor-initiating cells (TICs), also termed cancer stem cells (CSCs) are involved in breast cancer chemoresistance, metastasis and disease progression. To pinpoint tumor cell vulnerabilities and transcriptional drivers of therapeutic relevance, we have characterized the triple negative breast cancer (TNBC) CSC transcriptional landscape using epigenome mapping and nucleosome occupancy determination. We identify a set of transcriptional regulators and signaling mediators that enforce the cancer stem cell state and instruct potential therapeutic strategies. The basal epithelial marker, integrin-β4 (ITGB4), can be used to stratify mesenchymal-like triple-negative breast cancer (TNBC) cells into populations of low and high tumor-initiating ability in vivo. We used ChIP-seq to measure H3K27ac occupancy and map the transcriptional enhancers in SUM159 cells segregated into ITGB4HI (High tumor initiating ability) and ITGB4LOW (Low tumor initiating ability) populations. Gene-enhancer linking and comparative analysis of enhancer usage revealed an epigenomically defined set of genes that are candidate drivers of the CSC cell state, including GSK3β, DNA-binding transcription factors and cellular adhesion proteins. To further define the chromatin architecture and transcriptional regulatory circuitry that underlies CSC state, we deployed ATAC-seq (Assay for Transposase-Accessible Chromatin with high throughput sequencing) within ITGB4HI and ITGB4LOW populations. By pairing nucleosome occupancy and transcription factor kinetics, we created enhancer-linked transcriptional regulatory circuitry of these tumor-initiating cells. Together, the isolation of partially mesenchymal ITGB4HI CSCs, coupled with enhancer mapping and distillation of transcriptional regulatory circuitry from these cells enable the identification of cancer vulnerabilities and therapeutic opportunities for high-risk patients with TNBC. Citation Format: Guenther MG, Lambert AW, Chen MW, Fiore C, Eaton M, Orlando D, Bierie B, Weinberg RA, Fritz CC, Olson ER. Epigenomic analysis of cancer stem cell (CSC)-enriched triple-negative breast cancer (TNBC) populations reveals gene regulatory circuitry and novel tumor cell vulnerabilities [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-04-03.