Chromatin Regulators Mediate Anthracycline Sensitivity in Breast Cancer

Anthracyclines are a highly effective component of curative breast cancer chemotherapy, but are associated with significant morbidity(1,2). Since anthracyclines work in part via inhibition of topoisomerase-II (TOP2) on accessible DNA(3,4), we hypothesized that chromatin regulatory genes (CRGs) that mediate DNA accessibility might predict anthracycline response. We elucidate the role of CRGs in anthracycline sensitivity in breast cancer through integrative analysis of patient and cell line data. We identify a consensus set of 38 CRGs associated with anthracycline response across ten cell line datasets. Evaluating the interaction between expression and treatment in predicting survival in a metacohort of 1006 early-stage breast cancer patients, we identify 54 CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups, 12 of which overlapped with those identified in vitro. CRGs that promote DNA accessibility, including Trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility such as Polycomb complex proteins, were associated with decreased anthracycline sensitivity. We show that KDM4B modulates TOP2 accessibility to chromatin, elucidating a mechanism of TOP2 inhibitor sensitivity. These findings indicate that CRGs mediate anthracycline benefit by modulating DNA accessibility with implications for breast cancer patient stratification and treatment decision making.