Epigenetic and Transcriptomic Profiling of Mammary Gland Development and Tumor Models Disclose Regulators of Cell State Plasticity

Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during mammary development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells. In both mouse and human tumors, SOX10 expression correlates with stem/progenitor identity, dedifferentiation, and invasive characteristics. Strikingly, we demonstrate that SOX10 binds to genes that regulate neural crest cell identity, and that SOX10-positive tumor cells exhibit neural crest cell features. [Display omitted] •Developmental changes reveal mammary differentiation state regulators•Multi-lineage differentiation potential is evident in adult basal mammary cells•SOX10+ expression correlates with mammary tumor cell state plasticity•SOX10 activity can elicit neural crest-like features in mammary tumors Dravis et al. use chromatin accessibility assays and transcriptional profiling during mammary development to identify factors that mediate breast cancer cell state interconversions and find SOX10 as a key factor. Mammary tumor cells expressing high SOX10 acquire a motile, neural crest-like state.