Progesterone-RankL paracrine signaling has been proposed as a driver of stem cell expansion in the mammary gland, and Elf5 is essential for the differentiation of mammary epithelial progenitor cells. We demonstrate that Elf5 expression is induced by progesterone and that Elf5 and progesterone cooperate to promote alveolar development. The progesterone receptor and Elf5 are expressed in a mutually exclusive pattern, and we identify RankL as the paracrine mediator of the effects of progesterone on Elf5 expression in CD61+ progenitor cells and their consequent differentiation. Blockade of RankL action prevented progesterone-induced side branching and the expansion of Elf5+ mature luminal cells. These findings describe a mechanism by which steroid hormones can produce the expansion of steroid hormone receptor-negative mammary epithelial cells.
Funding
Funded by The National Health and Medical Research Council of Australia, by New South Wales Cancer Council, by Cancer Institute New South Wales, by Banque Nationale de Paris-Paribas Australia and New Zealand, by RT Hall Trust, by Australian Cancer Research Foundation, and by the National Breast Cancer Foundation and Cure Cancer Foundation Australia. J.M.P. is supported by the Institute of Molecular Biotechnology and an Advanced European Research Council grant from the European Union. J.M.P. holds an Innovator Award from Era of Hope/DoD [US Army Medical Research and Materiel Command Award Number W81XWH-12-1-0093].
