Role of PTHrp in Epithelial Stromal Interactions During Breast Development

摘要

We have previously shown that PTHrP is necessary for mammary development. Our studies have suggested that PTHrP is involved in regulating epitheial-mesenchymal interactions during both embryonic development as well as ductal outgowth during adolescence. It is our hypothesis that PTHrP is an epithelial signals that modulates the ability of the mammary mesenchyme to support epithelial morphogenesis. Over the three years of this project, we have generated data to support this hypothesis. We have shown that PTHrP, and its receptor PPfli, are expressed in an epithelial- mesenchymal pattern throughout mammary development. In addition, we have demonstrated that PTHrP signaling from the mammary epithelium is necessary for the proper differentiation of the mammary mesenchyme. We have also demonstrated that PTHrP is involved in regulating hormonally-stimulated growth at the terminal endbud during puberty. Finally, using a tetracycline regulated double transgenic mouse we have shown that PTHrP-overexpression before birth casues defects in the branching pattern of the epithelial ducts during puberty, while PTHrP overexpression after birth causes defects in ductai elongation during puberty. These results suggest that PTHrP may have a dual role in mammary development, Before birth, PTHrP may be involved in altering the differentiation of the dense mammary mesenchyme allowing it to support subsequent branching morphogeesis of the epithelium. After birth, PTHrP is involved in regulating cellular proliferation at the terminal end bud during puberty. Together these results support our hypothesis that PTHrP is an epithelial signal that modulates mammary stromal cell function during both embryonic development, as well as adolescent development of the mammary gland.