The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

Dalya Ataca, Patrick Aouad, Céline Constantin, Csaba Laszlo, Manfred Beleut, Marie Shamseddin, Renuga Devi Rajaram, Rachel Jeitziner, Timothy J. Mead, Marian Caikovski, Philipp Bucher, Giovanna Ambrosini, Suneel S. Apte and Cathrin Brisken ()
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Dalya Ataca: Ecole Polytechnique Fédérale de Lausanne
Patrick Aouad: Ecole Polytechnique Fédérale de Lausanne
Céline Constantin: Ecole Polytechnique Fédérale de Lausanne
Csaba Laszlo: Ecole Polytechnique Fédérale de Lausanne
Manfred Beleut: Ecole Polytechnique Fédérale de Lausanne
Marie Shamseddin: Ecole Polytechnique Fédérale de Lausanne
Renuga Devi Rajaram: Ecole Polytechnique Fédérale de Lausanne
Rachel Jeitziner: Ecole Polytechnique Fédérale de Lausanne
Timothy J. Mead: Cleveland Clinic Lerner Research Institute
Marian Caikovski: Ecole Polytechnique Fédérale de Lausanne
Philipp Bucher: Ecole Polytechnique Fédérale de Lausanne
Giovanna Ambrosini: Ecole Polytechnique Fédérale de Lausanne
Suneel S. Apte: Cleveland Clinic Lerner Research Institute
Cathrin Brisken: Ecole Polytechnique Fédérale de Lausanne

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Estrogens and progesterone control breast development and carcinogenesis via their cognate receptors expressed in a subset of luminal cells in the mammary epithelium. How they control the extracellular matrix, important to breast physiology and tumorigenesis, remains unclear. Here we report that both hormones induce the secreted protease Adamts18 in myoepithelial cells by controlling Wnt4 expression with consequent paracrine canonical Wnt signaling activation. Adamts18 is required for stem cell activation, has multiple binding partners in the basement membrane and interacts genetically with the basal membrane-specific proteoglycan, Col18a1, pointing to the basement membrane as part of the stem cell niche. In vitro, ADAMTS18 cleaves fibronectin; in vivo, Adamts18 deletion causes increased collagen deposition during puberty, which results in impaired Hippo signaling and reduced Fgfr2 expression both of which control stem cell function. Thus, Adamts18 links luminal hormone receptor signaling to basement membrane remodeling and stem cell activation.

Date: 2020
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DOI: 10.1038/s41467-020-15357-y

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