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
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
Stem Cell Reports. 2015 Mar 10;4(3):313-322. doi: 10.1016/j.stemcr.2015.01.011. Epub 2015 Feb 19.
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 (CD24CD49f) and luminal (CD24CD49f) subsets. This is accompanied by a marked reduction in CD49bSCA-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.
孕酮通过目前尚未完全了解的旁分泌机制驱动乳腺干细胞和祖细胞的动态变化。在此，我们证明基质衍生因子1（SDF-1；CXC12）的受体CXCR4是激素诱导的乳腺干细胞和祖细胞功能的关键调节因子。孕酮在基底和管腔乳腺上皮细胞群的转录组中引发特定变化，其中CXCL12和CXCR4代表一个假定的配体-受体对。在原位，CXCL12定位于孕酮受体阳性的管腔细胞，而CXCR4在基底和管腔隔室中以孕酮依赖的方式被诱导。CXCR4信号的药理学抑制消除了孕酮指导的基底（CD24CD49f）和管腔（CD24CD49f）亚群的扩增。这伴随着CD49bSCA-1管腔祖细胞、其功能能力以及小叶腺泡形成的显著减少。这些发现揭示了CXCL12和CXCR4是成年乳腺中激素信号传导的新型旁分泌效应器，并为潜在靶向乳腺癌中祖细胞生长和恶性转化提供了一条新途径。
