A Progesterone-CXCR4 Axis Controls Mammary Progenitor Cell Fate in the Adult Gland

• Published in: Stem cell reports Vol. 4; no. 3; pp. 313 - 322
• Main Authors: Shiah, Yu-Jia, Tharmapalan, Pirashaanthy, Casey, Alison E., Joshi, Purna A., McKee, Trevor D., Jackson, Hartland W., Beristain, Alexander G., Chan-Seng-Yue, Michelle A., Bader, Gary D., Lydon, John P., Waterhouse, Paul D., Boutros, Paul C., Khokha, Rama
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.03.2015; Elsevier
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2015.01.011

Progesterone drives mammary stem and progenitor cell dynamics through paracrine mechanisms that are currently not well understood. Here, we demonstrate that CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), is a crucial instructor of hormone-induced mammary stem and progenitor cell function. Progesterone elicits specific changes in the transcriptome of basal and luminal mammary epithelial populations, where CXCL12 and CXCR4 represent a putative ligand-receptor pair. In situ, CXCL12 localizes to progesterone-receptor-positive luminal cells, whereas CXCR4 is induced in both basal and luminal compartments in a progesterone-dependent manner. Pharmacological inhibition of CXCR4 signaling abrogates progesterone-directed expansion of basal (CD24+CD49fhi) and luminal (CD24+CD49flo) subsets. This is accompanied by a marked reduction in CD49b+SCA-1− luminal progenitors, their functional capacity, and lobuloalveologenesis. These findings uncover CXCL12 and CXCR4 as novel paracrine effectors of hormone signaling in the adult mammary gland, and present a new avenue for potentially targeting progenitor cell growth and malignant transformation in breast cancer. [Display omitted] •Progesterone induces distinct molecular programs in mammary cell compartments•CXCR4 induction occurs in lobuloalveoli and is progesterone dependent•CXCR4 inhibition abrogates luminal progenitor expansion and mammopoiesis•Targeting of the CXCL12-CXCR4 axis may limit mammary progenitor cell transformation In this article, Khokha and colleagues use expression profiling and functional assays to identify CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), as a crucial instructor of hormone-induced mammary stem and progenitor cell function. Pharmacological inhibition of CXCR4 signaling abrogates progesterone-directed expansion of basal and luminal subsets, resulting in a marked reduction in CD49b+SCA-1− luminal progenitors and their functional capacity, and lobuloalveologenesis.