CXCL12-CXCR7 SIGNALING AXIS REGULATES MAMMARY STEM CELLS IN NORMAL MAMMARY GLAND DEVELOPMENT

Abstract

Mammary stem cells (MaSCs) reside at the top of the differentiation hierarchy within the mammary epithelium and are key drivers of mammary gland development. Although MaSCs share transcriptional regulators and differentiation mechanisms with breast cancer stem cells (BCSCs), the microenvironmental factors governing their regulation are still unclear. Previous literature has implicated the importance of paracrine signaling between the basal and luminal mammary epithelial layers in promoting mammary gland morphogenesis, but there is a lack of studies investigating the exact signaling molecules and comprehensive mechanisms involved. Therefore, this study examines the role of homeostatic chemokines in affecting mammary gland development and MaSC activity. Through microarray gene expression data, we identified luminal-expressing chemokine ligand, CXCL12, and its basal-expressing chemokine receptor, CXCR7. After validating the protein expression of these chemokines, we investigated their functions through the generation of luminal-specific CXCL12 and basal-specific CXCR7 knockout mice. Our results ultimately demonstrate the importance of the CXCL12-CXCR7 signaling axis in promoting ductal branching morphogenesis, mammary epithelial cell proliferation, and MaSC activity. Furthermore, we found evidence for the existence of bidirectional crosstalk between the luminal and basal layers, once again mediated by signaling between CXCL12 and CXCR7. In addition to highlighting a novel role for CXCL12 and CXCR7 in regulating MaSCs during mammary gland development, our results have future implications in the initiation of breast cancer tumorigenesis by BCSCs. This study will thus provide a foundation for the future identification of homeostatic chemokines as new therapeutic targets for breast cancer therapy.