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.
Highlights
Estrogens and progesterone control breast development and carcinogenesis via their cognate receptors expressed in a subset of luminal cells in the mammary epithelium
By which progesterone receptor (PR) signaling in luminal mammary epithelial cells may elicit extracellular matrix (ECM) changes, we sought genes induced in vivo by progesterone treatment[22,23] that fulfilled two criteria: (1) They encoded secretory proteins and (2) They showed delayed induction by progesterone as expected of any indirect PR target which is expressed by myoepithelial cells and can directly interact with the basement membrane (BM)
Adamts[18] expression in the mammary epithelium is developmentally regulated, and its mRNA is enriched in myoepithelial cells, making it an attractive candidate to mediate ECM changes downstream of epithelial hormone action
Summary
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. Hedgehog signaling acts via Gli[2] downstream of growth hormone receptor signaling in fibroblasts to trigger changes in paracrine signaling and ECM proteins that affect stem cell function[10]. This suggests that stromal fibroblasts are part of the niche under direct endocrine control by growth hormone. We show that Adamts[18] provides a mechanistic link between epithelial steroid hormone receptor signaling and changes in the ECM, in particular the BM, that regulate mammary epithelial stemness
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