Single-cell multi-omic profiling of heterogeneous PROCR+ cells in mouse mammary gland and its implication for breast cancer

Abstract

Summary Protein C receptor (PROCR) marks a rare population of mammary epithelial cells with stem-like properties, but their low abundance has hindered characterization of their functional diversity and regulatory programs. Here, we integrate targeted enrichment with single-cell transcriptomic and chromatin accessibility profiling to construct a multimodal atlas of PROCR+ cells across development. We identify heterogeneous PROCR+ subpopulations, including a Procr+, Cdh5–, Col1a1+ population with features consistent with a mammary stem cell (MaSC) state, such as high developmental potency, an EMT-associated program, and an early differentiation position. Integrative analyses reveal dynamic transcriptional regulatory circuits underlying stemness and lineage commitment. Cross-species comparisons uncover analogous PROCR+ populations in human mammary epithelium, and this stem cell-like signature is enriched in triple-negative and claudin-low tumors. Together, these findings refine the mammary epithelial hierarchy, define regulatory programs underlying stemness and lineage bifurcation, and establish a molecular link between a distinct MaSC state and tumor aggressiveness.