title: RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1.
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.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
authors.forename: Purna A
authors.initials: PA
authors.lastname: Joshi
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Waterhouse
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Kannan
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
authors.forename: Swami
authors.initials: S
authors.lastname: Narala
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Di Grappa
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
authors.forename: Hartland W
authors.initials: HW
authors.lastname: Jackson
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z1L3, Canada.
authors.forename: Connie
authors.initials: C
authors.lastname: Eaves
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada. Electronic address: rama.khokha@utoronto.ca.
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology*; D019699:Thrombospondins / Q000096:biosynthesis / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C518903:RSPO1 protein, mouse; D053246:Receptor Activator of Nuclear Factor-kappa B; D019699:Thrombospondins; C505687:Tnfrsf11a protein, mouse