PR+ progenitors contribute to all mammary epithelial lineages

ABSTRACT The central role of progesterone in breast biology and cancer is undeniable. Progesterone is a potent mitogen for mammary stem cell expansion and essential for mammopoiesis, yet only a fraction of the luminal epithelium is described to express the progesterone receptor (PR). Progestins in contraceptives and HRT regimens increases breast cancer risk, whilst progesterone inhibition reduces mammary tumorigenesis. Understanding PR within mammary epithelial dynamics is imperative, especially given mammary stem/progenitors cells are the cells-of-origin in breast cancer. Here, we show PR-primed progenitors contribute to both mammary lineages and expose a novel PR+ basal population, challenging current dogma in the field. PR lineage-tracing yields an unprecedented contribution to the luminal and basal compartments. We uncover an asymmetrically dividing PR-primed subpopulation, which has unique bipotent clonogenic capacity and forms TEB-like outgrowths upon transplantation. We enumerate PR+ basal cells and dissect their proteomic landscape, establishing PR+ basal cells as a discrete basal subset, disparate from luminal PR+ cells. Finally, we identify PR+ basal cells in multiple proteomes, scRNAseq datasets and localize PR in clinical breast specimens. This forms a new foundation for comprehending hormone receptor patterning in the breast, not only based on lineage-identity but also the progenitor-progeny hierarchy. Our study shifts the current paradigm of breast biology with implications for breast cancer treatment given the growing interest in anti-progestin based primary prevention strategies.