A Progesterone-CXCR4 Axis Controls Mammary Progenitor Cell Fate in the Adult Gland

Yu-Jia Shiah; Pirashaanthy Tharmapalan; Alison E. Casey; Purna A. Joshi; Trevor D. McKee; Hartland W. Jackson; Alexander G. Beristain; Michelle A. Chan-Seng-Yue; Gary D. Bader; John P. Lydon; Paul D. Waterhouse; Paul C. Boutros; Rama Khokha

doi:10.1016/j.stemcr.2015.01.011

Stem Cell Reports (Mar 2015)

A Progesterone-CXCR4 Axis Controls Mammary Progenitor Cell Fate in the Adult Gland

Yu-Jia Shiah,
Pirashaanthy Tharmapalan,
Alison E. Casey,
Purna A. Joshi,
Trevor D. McKee,
Hartland W. Jackson,
Alexander G. Beristain,
Michelle A. Chan-Seng-Yue,
Gary D. Bader,
John P. Lydon,
Paul D. Waterhouse,
Paul C. Boutros,
Rama Khokha

Affiliations

Yu-Jia Shiah: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada
Pirashaanthy Tharmapalan: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada
Alison E. Casey: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
Purna A. Joshi: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
Trevor D. McKee: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
Hartland W. Jackson: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada
Alexander G. Beristain: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
Michelle A. Chan-Seng-Yue: Informatics and Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
Gary D. Bader: Department of Molecular Genetics, Medical Science Building, University of Toronto, Toronto, ON M5S 1A8, Canada
John P. Lydon: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Paul D. Waterhouse: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada
Paul C. Boutros: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada
Rama Khokha: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada

DOI: https://doi.org/10.1016/j.stemcr.2015.01.011
Journal volume & issue: Vol. 4, no. 3
pp. 313 – 322

Abstract

Read online

Progesterone drives mammary stem and progenitor cell dynamics through paracrine mechanisms that are currently not well understood. Here, we demonstrate that CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), is a crucial instructor of hormone-induced mammary stem and progenitor cell function. Progesterone elicits specific changes in the transcriptome of basal and luminal mammary epithelial populations, where CXCL12 and CXCR4 represent a putative ligand-receptor pair. In situ, CXCL12 localizes to progesterone-receptor-positive luminal cells, whereas CXCR4 is induced in both basal and luminal compartments in a progesterone-dependent manner. Pharmacological inhibition of CXCR4 signaling abrogates progesterone-directed expansion of basal (CD24+CD49fhi) and luminal (CD24+CD49flo) subsets. This is accompanied by a marked reduction in CD49b+SCA-1− luminal progenitors, their functional capacity, and lobuloalveologenesis. These findings uncover CXCL12 and CXCR4 as novel paracrine effectors of hormone signaling in the adult mammary gland, and present a new avenue for potentially targeting progenitor cell growth and malignant transformation in breast cancer.

Published in Stem Cell Reports

ISSN: 2213-6711 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.cell.com/stem-cell-reports/home

About the journal