AbstractBackgroundEpithelial stem cells (ESCs) demonstrate a capacity to maintain normal tissues homeostasis and ESCs with a deregulated behavior can contribute to cancer development. The ability to reprogram normal tissue epithelial cells into prostate or mammary stem‐like cells holds great promise to help understand cell of origin and lineage plasticity in prostate and breast cancers in addition to understanding normal gland development. We previously showed that an intracellular chemokine, CXCL12γ induced cancer stem cells and neuroendocrine characteristics in both prostate and breast adenocarcinoma cell lines. However, its role in normal prostate or mammary epithelial cell fate and development remains unknown. Therefore, we sought to elucidate the functional role of CXCL12γ in the regulation of ESCs and tissue development.MethodsProstate epithelial cells (PNT2) or mammary epithelial cells (MCF10A) with overexpressed CXCL12γ was characterized by quantitative real‐time polymerase chain reaction, Western blots, and immunofluorescence for lineage marker expression, and fluorescence activated cell sorting analyses and sphere formation assays to examine stem cell surface phenotype and function. Xenotransplantation animal models were used to evaluate gland or acini formation in vivo.ResultsOverexpression of CXCL12γ promotes the reprogramming of cells with a differentiated luminal phenotype to a nonluminal phenotype in both prostate (PNT2) and mammary (MCF10A) epithelial cells. The CXCL12γ‐mediated nonluminal type cells results in an increase of epithelial stem‐like phenotype including the subpopulation of EPCAMLo/CD49fHi/CD24Lo/CD44Hi cells capable of sphere formation. Critically, overexpression of CXCL12γ promotes the generation of robust gland‐like structures from both prostate and mammary epithelial cells in in vivo xenograft animal models.ConclusionsCXCL12γ supports the reprogramming of epithelial cells into nonluminal cell‐derived stem cells, which facilitates gland development.