A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway.

ABSTRACT: The microenvironment provides cues that control the behavior of epithelial stem and progenitor cells. Here, we identify matrix metalloproteinase-3 (MMP3) as a regulator of Wnt signaling and mammary stem cell (MaSC) activity. We show that MMP3 overexpression promotes hyperplastic epithelial growth, surprisingly, in a nonproteolytic manner via its hemopexin (HPX) domain. We demonstrate that MMP3-HPX specifically binds and inactivates Wnt5b, a noncanonical Wnt ligand that inhibits canonical Wnt signaling and mammary epithelial outgrowth in vivo. Indeed, transplants overexpressing MMP3 display increased canonical Wnt signaling, demonstrating that MMP3 is an extracellular regulator of the Wnt signaling pathway. MMP3-deficient mice exhibit decreased MaSC populations and diminished mammary-recons

SUBMITTER: Kessenbrock K 

PROVIDER: S-EPMC3769456 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature