Multiple actions of parathyroid hormone-related protein in breast cancer bone metastasis.

The sequence similarity within the amino-terminal regions of parathyroid hormone (PTH) and PTH-related protein (PTHrP) allows the two to share actions at a common site, the PTH1 receptor. A number of biological activities have been ascribed to actions of other domains within PTHrP. PTHrP production by late stage breast cancer has been shown to contribute to bone metastasis formation through promotion of osteoclast formation and bone resorption by action through PTH1 receptors. There is evidence also for a role for PTHrP early in breast cancer that is protective against tumour progression. No signalling pathway has been identified for this effect. PTHrP has also been identified as a factor promoting the emergence of breast cancer cells from dormancy in bone. In that case, PTHrP does not function through activation of PTH1 receptors, despite having very substantial effects on transcriptional activity of the breast cancer cells. This indicates actions of PTHrP that are non-canonical, that is, mediated through domains other than the amino-terminal. It is concluded that PTHrP has several distinct paracrine, autocrine, and intracrine actions in the course of breast cancer pathophysiology. Some are mediated through action at PTH1 receptors and others are controlled by other domains within PTHrP. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.