Parathyroid hormone related protein (PTHrP) is a normal product of mammary epithelial cells, and previous studies have demonstrated that targeted over- or under expression of PTHrP leads to severe defects in its development. We have previously shown that transient over expression of PTHrP before birth causes defects in ductal side branching during puberty, while over expression of PTHrP during puberty causes defects in estrogen induced ductal proliferation. These findings suggest that PTHrP has a dual role in mammary development. Before birth PTHrP is involved in determining the subsequent pattern of epithelial branching during puberty. After birth, PTHrP is involved in regulating estrogen induced ductal elongation. Preliminary evidence suggests that both of these defects are due to PTHrP signaling in the mammary stroma. It is our hypothesis that PTHrP is an epithelial cell product that modulates mammary stromal cell function during epithelial-stromal interactions. We propose three specific aims that are aimed at elucidating the mechanisms by which PTHrP modulates the ability of mammary stromal cells to support the growth and morphogenesis of mammary epithelial cells during puberty. First, we will examine the effects of PTHrP on modulating the ability of the mammary stroma to support ductal branching of mammary epithelial cells. Second, we will examine the effects of PTHrP on the regulation of estrogen induced growth of mammary epithelial cells. Finally, we will examine the effects of PTHrP on EGFR signaling in the mammary gland. It is our expectation that the results from these experiments will lead to a greater understanding of the role of PTHrP in post-natal mammary development. In addition, this work will have a broad impact on science education at the undergraduate level, as the experiments described in this proposal have been designed specifically for undergraduate researchers. ? ?
