The Role of PTHrP in Mammary Gland Development and Tumorigenesis.

PTHrP was discovered as the tumor product responsible for the syndrome of humoral hypercalcemia of malignancy. Recent experiments have shown that PTHrP has important functions during development. This project is designed to explore the hypothesis that PTHrP is a locally-produced growth factor that regulates epithelial-mesenchymal interactions during mammary development. In the second year we gathered more evidence to support a critical role for PTHrP in the control of mammary stromal cell function during embryonic development. In the absence of PTHrP there is a loss of the androgen-mediated destruction of the mammary buds in male embryos due to a failure of androgen receptor expression by the mesenchymal cells. In addition, there is also a failure of Tenascin C expression in PTHrP and PTHPTHrP receptor knockout mammary buds. These results demonstrate that PTHrP is necessary for the proper differentiation of the mesenchyme. We have also found that PTHrP appears to regulate mammary stromal cell function during adolescence and pregnancy. Finally, although overexpression of PTHrP inhibits hormonally-induced ductular proliferation during mammary development, it does not appear to inhibit mammary tumor formation, at least in the OR mouse model.