Abstract 2108: Chromatin state as a mechanism of anthracycline response in breast cancer

Abstract

Abstract The aim of this study is to determine the effect of chromatin regulators on anthracycline response in breast cancer. Anthracyclines are a highly effective component of curative breast cancer chemotherapy, but can be associated with substantial side effects. Because anthracyclines work in part via inhibition of topoisomerase II (TOP2) on accessible DNA, we hypothesized that expression levels of chromatin regulatory proteins that mediate DNA accessibility might predict anthracycline response. We used RNA-sequencing data from the TCGA breast cancer cohort to infer a breast cancer chromatin regulatory network using the ARACNE algorithm. A panel of 45 breast cancer cell lines with accompanying gene expression and growth inhibitory (GI50) data was used to build a genome-wide signature of anthracycline response. Based on the GI50, cell lines were classified as sensitive or resistant. The VIPER algorithm was then used to identify chromatin regulatory genes (CRGs) from the ARACNE network whose targets were significantly enriched in the anthracycline resistance signature. We further compiled a metacohort of 1006 clinically annotated early-stage breast cancer patients with gene expression data, allowing us to identify CRGs whose expression levels were associated with outcome after adjuvant treatment with anthracyclines. 24 CRGs associated (P<0.1) with anthracycline response in vitro and 54 CRGs associated (P<0.05) with anthracycline response in the patient cohort, 9 of which overlapped with the in vitro CRGs. In the patient cohort, CRG expression associated strongly with anthracycline response in all major subgroups of breast cancer (ER+/HER2-, HER2+, and triple-negative). In general, CRGs that promoted open chromatin (BAF and COMPASS) were, at high levels of expression, associated with anthracycline sensitivity, while CRGs associated with closed chromatin (PRC2) were, at high levels of expression, associated with anthracycline resistance. We functionally validated KDM4B as a predictor of anthracycline, but not taxane, sensitivity in a breast cancer cell line model through shRNA knockdown. We present a set of CRGs that control the chromatin accessibility in breast cancer both in vitro and in vivo; we infer that those tumors with more open chromatin as determined by the expression of these CRGs are intrinsically more sensitive to anthracyclines, while those with more closed chormatin are more resistant. Future work into the predictive power of these CRGs may allow us to target anthracyclines to only those patients who will benefit. Citation Format: Jose A. Seoane, Jacob G. Kirkland, Jennifer L. Caswell-Jin, Gerald R. Crabtree, Christina Curtis. Chromatin state as a mechanism of anthracycline response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2108.