Adult mammary stem cells remodel the mammary gland in development and pregnancy. The mammary stem cell population expands in response to extracellular signals such as Wnt. Extracellular zinc-dependent endopeptidases of the matrix metalloproteinase (MMPs) family are thought to promote tumour cell invasion and metastasis. Werb and colleagues have found that MMP3 modulates Wnt signalling to control mammary stem cell function (Cell Stem Cell http://doi.org/10/nfh; 2013). The authors showed that overexpression in mammary stem cells of the full-length MMP3, or of its hemopexin domain (HPX) (which binds MMP substrates but has no catalytic activity), leads to their hyperplastic growth when transplanted in mouse mammary fat pads. They also demonstrated that the mammary stem cell population is decreased in MMP3-deficient mice, and that it loses some of its reconstitution properties in vivo following transplantation.

Using a yeast two-hybrid approach, they identified the non-canonical Wnt ligand, Wnt5b, as an MMP3-HPX interactor. The authors showed that Wnt5b activates a non-canonical signalling pathway that positively regulates the transcription factor NFAT to inhibit mammary stem cell proliferation. However, as reported before of other non-canonical Wnt ligands, they also found that Wnt5b interferes with canonical Wnt–β-catenin signalling by occupying LRP5/6 co-receptors. Further analysis indicated that MMP3 binds to a Wnt5b domain overlapping the region that interacts with the co-receptors, providing insight into how MMP3 counteracts the action of Wnt5b to regulate mammary stem cell function.