title: Parathyroid hormone-related protein and bone metastases.
abstract: Parathyroid hormone-related protein (PTH-rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH-rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH-rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastatic to bone expresses PTH-rP in >90% of cases, compared with only 17% of metastasis to nonbone sites. These observations suggest that PTH-rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor-beta (TGF-beta), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH-rP expression and tumor cell growth. To investigate the role of PTH-rP in the pathophysiology of breast carcinoma metastasis to bone, the human breast carcinoma cell line MDA-MB-231 was studied in a murine model of human breast carcinoma metastasis to bone. A series of experiments were performed in which 1) PTH-rP secretion was altered, 2) the effects of PTH-rP were neutralized, or 3) the responsiveness to TGF-beta was abolished in MDA-MB-231 cells. Cultured MDA-MB-231 cells secreted low amounts of PTH-rP that increased fivefold in response to TGF-beta. Tumor cells inoculated into the left cardiac ventricle of nude mice caused osteolytic metastasis similar to that observed in humans with breast carcinoma. When PTH-rP was overexpressed in the tumor cells, bone metastases were increased. MDA-MB-231 cells transfected with the cDNA for human preproPTH-rP secreted a tenfold greater amount of PTH-rP and caused significantly greater bone metastases when inoculated into the left cardiac ventricle of female nude mice compared with parental cells. In contrast, when the biologic effects of PTH-rP were neutralized or its production was suppressed, such metastases were decreased. Treatment of mice with a neutralizing monoclonal antibody to human PTH-rP resulted in a decrease in the development and progression of bone metastasis due to the parental MDA-MB-231 cells. Similar results were observed when mice were treated with dexamethasone, a potent glucocorticoid that suppresses production of PTH-rP by the MDA-MB-231 cells in vitro. The role of bone-derived TGF-beta in the development and progression of bone metastasis was studied by transfecting MDA-MB-231 cells with a cDNA encoding a TGF-beta type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF-beta. Stable clones expressing this mutant receptor (MDA/TbetaRIIdeltacyt) did not increase PTH-rP secretion in response to TGF-beta stimulation compared with controls of untransfected MDA-MB-231 or those transfected with the empty vector. Mice inoculated into the left cardiac ventricle with MDA/TbetaRIIdeltacyt had fewer and smaller bone metastases as assessed radiographically and histomorphometrically compared with controls. Taken together, these data suggest that PTH-rP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Furthermore, TGF-beta responsiveness of breast carcinoma cells may be important for the expression of PTH-rP in bone and the development of osteolytic bone metastasis in vivo. These interactions define a critical feedback loop between breast carcinoma cells and the bone microenvironment that may be responsible for the alacrity with which breast carcinoma grows in bone.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, 78284-7877, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Guise
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary*; D016723:Bone Remodeling / Q000502:physiology; D001862:Bone Resorption / Q000209:etiology; D001943:Breast Neoplasms / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D016207:Cytokines; D009363:Neoplasm Proteins; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D016212:Transforming Growth Factor beta; D003907:Dexamethasone