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p190-B RhoGAP Regulates Mammary Ductal Morphogenesis

Department of Molecular & Cellular Biology (G.C., W.B., J.M.R.), Baylor College of Medicine, and Department of Pediatrics (D.H.), Children’s Nutrition Research Center, Houston, Texas 77030; and Massachusetts General Hospital Cancer Center and Harvard Medical School (J.S.), Charlestown, Massachusetts 02129

Address all correspondence and requests for reprints to: Dr. Jeffrey M. Rosen, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. E-mail: jrosen{at}bcm.tmc.edu.

Previous studies from our laboratory have demonstrated that p190-B RhoGAP (p190-B) is differentially expressed in the Cap cells of terminal end buds (TEBs) and poorly differentiated rodent mammary tumors. Based on these observations we hypothesized that p190-B might play an essential role in invasion of the TEBs into the surrounding fat pad during ductal morphogenesis. To test this hypothesis, mammary development was studied in p190-B-deficient mice. A haploinsufficiency phenotype was observed in p190-B heterozygous mice as indicated by decreased number and rate of ductal outgrowth(s) at 3, 4, and 5 wk of age when compared with their wild-type littermates. This appeared to result from decreased proliferation in the Cap cells of the TEBs, a phenotype remarkably similar to that observed previously in IGF-I receptor null mammary epithelium. Furthermore, decreased expression of insulin receptor substrates 1 and 2 were observed in TEBs of p190-B heterozygous mice. These findings are consistent with decreased IGF signaling observed previously in p190-B^-/- mouse embryo fibroblasts. To further assess if this defect was cell autonomous or due to systemic endocrine effects, the mammary anlagen from p190-B^+/+, p190-B^+/-, and p190-B^-/- mice was rescued by transplantation into the cleared fat pad of recipient Rag1^-/- mice. Surprisingly, as opposed to 75–80% outgrowths observed using wild-type donor epithelium, only 40% of the heterozygous and none of the p190-B^-/- epithelial transplants displayed any outgrowths. Together, these results suggest that p190-B regulates ductal morphogenesis, at least in part, by modulating the IGF signaling axis.

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