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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.

Author information

1
Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
2
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z1L3, Canada.
3
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
4
Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada. Electronic address: rama.khokha@utoronto.ca.

Abstract

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.

PMID:
26095608
PMCID:
PMC4618445
DOI:
10.1016/j.stemcr.2015.05.012
[Indexed for MEDLINE]
Free PMC Article

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