Beleut, M.RD, RajaramCaikovski, M.Ayyanan, A.Germano, D.Choi, Y.Schneider, P.Brisken, C.2010-03-192010-03-192010-03-19201010.1073/pnas.0915148107https://infoscience.epfl.ch/handle/20.500.14299/48302WOS:000274599500052The mouse mammary gland develops postnatally under the control of female reproductive hormones. Estrogens and progesterone trigger morphogenesis by poorly understood mechanisms acting on a subset of mammary epithelial cells (MECs) that express their cognate receptors, estrogen receptor α (ERα) and progesterone receptor (PR). Here, we show that in the adult female, progesterone drives proliferation of MECs in two waves. The first, small wave, encompasses PR(+) cells and requires cyclin D1, the second, large wave, comprises mostly PR(−) cells and relies on the tumor necrosis factor (TNF) family member, receptor activator of NF-κB-ligand (RANKL). RANKL elicits proliferation by a paracrine mechanism. Ablation of RANKL in the mammary epithelium blocks progesterone-induced morphogenesis, and ectopic expression of RANKL in MECs completely rescues the PR−/− phenotype. Systemic administration of RANKL triggers proliferation in the absence of PR signaling, and injection of a RANK signaling inhibitor interferes with progesterone-induced proliferation. Thus, progesterone elicits proliferation by a cell-intrinsic and a, more important, paracrine mechanism.cell proliferationcyclin D1mammary epitheliumprogesteroneRanklEstrogen-Receptor-AlphaBreast-CancerCell-ProliferationEpithelial-CellsLuminal-CellMice LackingDna StrandsB IsoformMouseExpressiontext::journal::journal article::research article