Parathyroid hormone-related protein (
PTHrP) is required for embryonic breast development and has important functions during lactation, when it is produced by alveolar epithelial cells and secreted into the maternal circulation to mobilize skeletal
calcium used for milk production.
PTHrP is also produced by breast
cancers, and GWAS studies suggest that it influences
breast cancer risk. However, the exact functions of
PTHrP in
breast cancer biology remain unsettled.
METHODS: We developed a
tetracycline-regulated, MMTV (mouse mammary tumor virus)-driven model of
PTHrP overexpression in mammary epithelial cells (Tet-
PTHrP mice) and bred these mice with the MMTV-PyMT (polyoma middle
tumor-antigen)
breast cancer model to analyze the impact of
PTHrP overexpression on normal mammary gland biology and in
breast cancer progression.
RESULTS: Overexpression of
PTHrP in
luminal epithelial cells caused alveolar
hyperplasia and secretory differentiation of the mammary epithelium with milk production. This was accompanied by activation of Stat5 and increased expression of E74-like factor-5 (Elf5) as well as a delay in post-lactation involution. In MMTV-PyMT mice, overexpression of
PTHrP (Tet-
PTHrP;PyMT mice) shortened
tumor latency and accelerated
tumor growth, ultimately reducing overall survival.
Tumors overproducing
PTHrP also displayed increased expression of nuclear pSTAT5 and Elf5, increased expression of markers of secretory differentiation and milk constituents, and histologically resembled secretory
carcinomas of the breast. Overexpression of
PTHrP within cells isolated from
tumors, but not
PTHrP exogenously added to cell
culture media, led to activation of STAT5 and
milk protein gene expression. In addition, neither ablating the Type 1
PTH/PTHrP receptor (PTH1R) in epithelial cells nor treating Tet-
PTHrP;PyMT mice with an anti-PTH1R antibody prevented secretory differentiation or altered
tumor latency. These data suggest that
PTHrP acts in a cell-autonomous, intracrine manner. Finally, expression of
PTHrP in human breast
cancers is associated with expression of genes involved in milk production and STAT5 signaling.
CONCLUSIONS: