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Stem Cell Reports. 2015 Jul 14;5(1):31-44. doi: 10.1016/j.stemcr.2015.05.012. Epub 2015 Jun 18.

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

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Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z1L3, Canada.
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada. Electronic address:


Systemic 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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