Chromatin Patterns Distinguish Breast Tumor Subtypes and Disease Progression in Association with ANP32E levels

Abstract

Despite highly advanced diagnosis and treatment strategies, breast cancer patient outcomes vary extensively, even among individuals with the same diagnosis. Thus, a better understanding of the unique molecular characteristics that underlie tumor trajectories and responses to therapy remains a central goal. We report that chromatin patterns represent an important characteristic, capable of stratifying tumor identity and progression. We find that patterns of chromatin accessibility can be classified into 3 major groups, representing Basal-like tumors, hormone receptor (HR)-expressing tumors, and invasive lobular Luminal-A tumors. Major chromatin differences occur throughout the genome at motifs for the transcription factor FOXA1 in HR-positive tumors, and motifs for SOX9 in Basal-like tumors. A large portion of lobular Luminal-A tumors display a chromatin signature defined by accessibility at FOXA1 binding motifs, distinguishing them from others within this subtype. Expression of the histone chaperone ANP32E is inversely correlated with tumor progression and chromatin accessibility at FOXA1 binding sites. Tumors with high levels of ANP32E exhibit an immune response and proliferative gene expression signature, whereas tumors with low ANP32E levels appear programmed for differentiation. Our results indicate that ANP32E may function through chromatin state regulation to control breast cancer differentiation and tumor plasticity.