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Elucidating the Tumor-Suppressive Role of SLITs in Maintaining the Basal Cell Niche
Final rept.1 Jul 2008-31 Sep 2011
CALIFORNIA UNIV SANTA CRUZ
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The research performed over the last thirty-nine months is based on the hypothesis that SLITROBO1 signaling regulates interactions between myoepithelial and luminal epithelial cells, and that loss of this activity results in the destabilization of the basal cell niche. Over the past 12 months, we have extended our analysis on the excess population of stem and progenitor cells discovered in Slit2--Slit3-- and Robo1-- mammary glands. We identified Robo1 as a target of TGF- 1, whose actions increase the levels of ROBO1 specifically in the basal compartment. This upregulation of SLITROBO1 signaling, in turn, inhibits canonical WNT signaling in the basal layer by regulating the subcellular localization of -catenin, reducing the proliferation of progenitor cells and ultimately reducing the number of myoepithelial cells. Since myoepithelial cells produce growth factors that stimulate branching, we show that the overall consequence of enhanced SLITROBO1 signaling is reduced branch formation. These studies identify a novel developmental role for SLITs in regulating cell proliferation and, as such, they provide a gratifying developmental correlate for the role of SLITs during tumorigenesis when they function to suppress tumor cell proliferation.
APPROVED FOR PUBLIC RELEASE