Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland |
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| Authors: | Manfred Beleut Renuga Devi Rajaram Marian Caikovski Ayyakkannu Ayyanan Davide Germano Yongwon Choi Pascal Schneider Cathrin Brisken |
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| Affiliation: | aEcole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute for Experimental Cancer Research (ISREC), NCCR Molecular Oncology, CH-1015 Lausanne, Switzerland; ;bUniversity Hospital Basel, CH-4031 Basel, Switzerland; ;cDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and ;dDepartment of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland |
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| Abstract: | The 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. |
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| Keywords: | cell proliferation cyclin D1 mammary epithelium progesterone RANKL |
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