Basal-like breast cancer originates in luminal progenitors, frequently with an altered PI3K pathway, and focally in close association with genetically altered myoepithelial cells at the site of tumor initiation. The exact trajectory behind this bi-lineage phenomenon remains poorly understood.

Here we used a breast cancer relevant transduction protocol including hTERT, shp16, shp53, and PIK3CA^H1047R to immortalize FACS isolated luminal cells, and we identified a candidate multipotent progenitor. Specifically, we identified a keratin 23 (K23)⁺/ALDH1A3⁺/CALML5⁻ ductal-like progenitor with the potential to differentiate into CALML5⁺ lobular-like cells. We found that the apparent luminal phenotype of these oncogene transduced progenitors was metastable giving rise to basal-like cells dependent on culture conditions. In 3D organoid culture and upon transplantation to mice the bipotent progenitor cell line organized into a bi-layered acinus-like structure reminiscent of that of the normal breast gland.

These findings provide proof of principle that progenitors within the human breast luminal epithelial compartment may serve as a source of correctly positioned myoepithelial cells. This may prove useful in assessing the role of myoepithelial cells in breast tumor progression.