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The myoepithelial (MEP) lineage of human breast comprises bipotent and multipotent progenitors in ducts and terminal duct lobular units (TDLUs). We here assess whether this heterogeneity impacts on oncogenic  PIK3CA  transformation. Single cell RNA sequencing (scRNA-seq) and multicolor imaging reveal that terminal ducts represent the most enriched source of cells with ductal MEP markers including α-smooth muscle actin (α-SMA), keratin K14, K17 and CD200. Furthermore, we find neighboring CD200 high  and CD200 low  progenitors within terminal ducts. When sorted and kept in ground state conditions, their CD200 low  and CD200 high  phenotypes are preserved. Upon differentiation, progenitors remain multipotent and bipotent, respectively. Immortalized progenitors are transduced with mutant  PIK3CA  on an shp53 background. Upon transplantation, CD200 low  MEP progenitors distinguish from CD200 high  by the formation of multilayered structures with a hyperplastic inner layer of luminal epithelial cells. We suggest a model with spatially distributed MEP progenitors as founder cells of biphasic breast lesions with implications for early detection and prevention strategies.

Myoepithelial progenitors as founder cells of hyperplastic human breast lesions upon PIK3CA transformation