RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1

•Luminal progenitors are targets of progesterone in the adult human breast•Progesterone-induced expansion of mammary epithelial subsets requires RANK•RANK signaling targets WNT-responsive ER–PR– luminal progenitors and basal cells•RANK controls RSPO1, which rescues defective progenitor expansion in Rank-null state

SummarySystemic and local signals must be integrated by mammary stem and progenitor cells to regulate their cyclic growth and turnover in the adult gland. Here, we show RANK-positive luminal progenitors exhibiting WNT pathway activation are selectively expanded in the human breast during the progesterone-high menstrual phase. To investigate underlying mechanisms, we examined mouse models and found that loss of RANK prevents the proliferation of hormone receptor-negative luminal mammary progenitors and basal cells, an accompanying loss of WNT activation, and, hence, a suppression of lobuloalveologenesis. We also show that R-spondin1 is depleted in RANK-null progenitors, and that its exogenous administration rescues key aspects of RANK deficiency by reinstating a WNT response and mammary cell expansion. Our findings point to a novel role of RANK in dictating WNT responsiveness to mediate hormone-induced changes in the growth dynamics of adult mammary cells.

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