PTHrP and breast cancer

Parathyroid hormone-related peptide (PTHrP) has a high homology with the N-terminal portion of the parathyroid hormone (PTH). The gene of PTHrP is complex and can generate by alternative splicing at least three mature peptides containing 139, 141 and 173 amino acids. PTHrP acts via a common receptor with PTH but also via specific receptors. In physiological circumstances, PTHrP is produced locally in many paracrine functions, particularly during embryonic normal tissues where it has autocrine/ development, growth regulation and differentiation of many cellular types. PTHrP has endocrine action on bone and kidney. The humoral hypercalcemia of malignancy is mainly mediated by PTHrP, Most hypercalcemic patients with solid tumors have increased plasma PTHrP, whereas PTHrP is not detectable in healthy subjects. During treatment with bisphosphonates, elevated plasma levels of PTHrP are associated with a weak response. PTHrP has also a significant role in the pathophysiology of bone metastases. PTHrP can induce a local osteolysis near the bone metastases, which favours their progression and thus participates in the autocrine regulation of tumor growth. In breast cancer, PTHrP is detected in about 60% of primary tumors and in more than 70% of bone metastases, whereas only Coo of nonbone metastases express PTHrP. A higher expression of PTHrP and its mRNA 1-139, is positively correlated with an invasive tumor phenotype and the development of bone metastases. PTHrP is an effector of transforming growth factor (TGF beta) in the development and progression of osteolytic hone metastases. TGF beta, which is released in bone matrix during osteolytic resorption, enhances tumor cells PTHrP production. Then, PTHrP stimulates bone resorption and develops tumor cells metastatic potential. Thus a feedback loop exists between carcinoma cell and the bone microenvironment, leading to a vicious circle.