OVEREXPRESSION OF PARATHYROID HORMONE-RELATED PROTEIN OR PARATHYROID-HORMONE IN TRANSGENIC MICE IMPAIRS BRANCHING MORPHOGENESIS DURING MAMMARY-GLAND DEVELOPMENT

Parathyroid hormone-related protein (PTHrP) was originally discovered as the tumor product that causes humoral hypercalcemia of malignancy; PTHrP is now known to be widely expressed in many normal fetal tissues where it may participate in the regulation of organogenesis. In this report, we document that overexpression of PTHrP in myoepithelial cell s in the mammary glands of transgenic mice resulted in a form of breas t hypoplasia characterized by a profound defect in branching morphogen esis of the developing mammary duct system, In addition, transgenic mi ce manifested a defect in lobuloalveolar development during pregnancy that seemed to be, in part, the consequence of an impaired ability to form terminal ducts in response to estrogen and progesterone stimulati on, The effects of PTHrP on branching morphogenesis during breast deve lopment appeared to be the result of aminoterminal PTH-like sequences that signal through the PTH/PTHrP receptor, since overexpression of pa rathyroid hormone itself in the mammary glands of transgenic mice caus ed a similar developmental phenotype, and delivery of PTHrP (1-36) via locally implanted slow-release pellets impaired breast development in normal mice. These results suggest that PTHrP, which is a native prod uct of mammary epithelial and myoepithelial cells may participate in n ormal breast development, perhaps as a locally secreted growth inhibit or.