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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Oct 1, 1996; 98(7): 1544–1549.
PMCID: PMC507586

Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis.

Abstract

Breast cancer almost invariably metastasizes to bone in patients with advanced disease and causes local osteolysis. Much of the morbidity of advanced breast cancer is a consequence of this process. Despite the importance of the problem, little is known of the pathophysiology of local osteolysis in the skeleton or its prevention and treatment. Observations in patients with bone metastases suggest that breast cancer cells in bone express parathyroid hormone-related protein (PTHrP) more frequently than in soft tissue sites of metastasis or in the primary tumor. Thus, the role of PTHrP in the causation of breast cancer metastases in bone was examined using human breast cancer cell lines. Four of eight established human breast cancer cell lines expressed PTHrP and one of these cell lines, MDA-MB-231, was studied in detail using an in vivo model of osteolytic metastases. Mice inoculated with MDA-MB-231 cells developed osteolytic bone metastasis without hypercalcemia or increased plasma PTHrP concentrations. PTHrP concentrations in bone marrow plasma from femurs affected with osteolytic lesions were increased 2.5-fold over corresponding plasma PTHrP concentrations. In a separate experiment, mice were treated with either a monoclonal antibody directed against PTHrP(1-34), control IgG, or nothing before tumor inoculation with MDA-MB-231 and twice per week for 26 d. Total area of osteolytic lesions was significantly lower in mice treated with PTHrP antibodies compared with mice receiving control IgG or no treatment. Histomorphometric analysis of bone revealed decreased osteoclast number per millimeter of tumor/bone interface and increased bone area, as well as decreased tumor area, in tumor-bearing animals treated with PTHrP antibodies compared with respective controls. These results indicate that tumor-produced PTHrP can cause local bone destruction in breast cancer metastatic to bone, even in the absence of hypercalcemia or increased circulating plasma concentrations of PTHrP. Thus, PTHrP may have an important pathogenetic role in the establishment of osteolytic bone lesions in breast cancer. Neutralizing antibodies to PTHrP may reduce the development of destructive bone lesions as well as the growth of tumor cells in bone.

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Selected References

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  • Boyde A, Maconnachie E, Reid SA, Delling G, Mundy GR. Scanning electron microscopy in bone pathology: review of methods, potential and applications. Scan Electron Microsc. 1986;(Pt 4):1537–1554. [PubMed]
  • Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer. 1987 Jan;55(1):61–66. [PMC free article] [PubMed]
  • Stewart AF, Horst R, Deftos LJ, Cadman EC, Lang R, Broadus AE. Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med. 1980 Dec 11;303(24):1377–1383. [PubMed]
  • Burtis WJ, Brady TG, Orloff JJ, Ersbak JB, Warrell RP, Jr, Olson BR, Wu TL, Mitnick ME, Broadus AE, Stewart AF. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med. 1990 Apr 19;322(16):1106–1112. [PubMed]
  • Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, Bennett RC, Martin TJ. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res. 1991 Jun 1;51(11):3059–3061. [PubMed]
  • Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, Bennett RC, Martin TJ. Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res. 1990 Dec 1;50(23):7710–7716. [PubMed]
  • Bundred NJ, Ratcliffe WA, Walker RA, Coley S, Morrison JM, Ratcliffe JG. Parathyroid hormone related protein and hypercalcaemia in breast cancer. BMJ. 1991 Dec 14;303(6816):1506–1509. [PMC free article] [PubMed]
  • Guise TA, Yoneda T, Yates AJ, Mundy GR. The combined effect of tumor-produced parathyroid hormone-related protein and transforming growth factor-alpha enhance hypercalcemia in vivo and bone resorption in vitro. J Clin Endocrinol Metab. 1993 Jul;77(1):40–45. [PubMed]
  • Cailleau R, Young R, Olivé M, Reeves WJ., Jr Breast tumor cell lines from pleural effusions. J Natl Cancer Inst. 1974 Sep;53(3):661–674. [PubMed]
  • Sato K, Yamakawa Y, Shizume K, Satoh T, Nohtomi K, Demura H, Akatsu T, Nagata N, Kasahara T, Ohkawa H, et al. Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors. J Bone Miner Res. 1993 Jul;8(7):849–860. [PubMed]
  • Arguello F, Baggs RB, Frantz CN. A murine model of experimental metastasis to bone and bone marrow. Cancer Res. 1988 Dec 1;48(23):6876–6881. [PubMed]
  • Pandian MR, Morgan CH, Carlton E, Segre GV. Modified immunoradiometric assay of parathyroid hormone-related protein: clinical application in the differential diagnosis of hypercalcemia. Clin Chem. 1992 Feb;38(2):282–288. [PubMed]
  • Budayr AA, Nissenson RA, Klein RF, Pun KK, Clark OH, Diep D, Arnaud CD, Strewler GJ. Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia. Ann Intern Med. 1989 Nov 15;111(10):807–812. [PubMed]
  • Grill V, Ho P, Body JJ, Johanson N, Lee SC, Kukreja SC, Moseley JM, Martin TJ. Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab. 1991 Dec;73(6):1309–1315. [PubMed]
  • Burtis WJ, Wu T, Bunch C, Wysolmerski JJ, Insogna KL, Weir EC, Broadus AE, Stewart AF. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987 May 25;262(15):7151–7156. [PubMed]
  • Strewler GJ, Stern PH, Jacobs JW, Eveloff J, Klein RF, Leung SC, Rosenblatt M, Nissenson RA. Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. J Clin Invest. 1987 Dec;80(6):1803–1807. [PMC free article] [PubMed]
  • Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall RE, Kemp BE, Suva LJ, Rodda CP, Ebeling PR, Hudson PJ, Zajac JD, et al. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci U S A. 1987 Jul;84(14):5048–5052. [PMC free article] [PubMed]
  • Bundred NJ, Walker RA, Ratcliffe WA, Warwick J, Morrison JM, Ratcliffe JG. Parathyroid hormone related protein and skeletal morbidity in breast cancer. Eur J Cancer. 1992;28(2-3):690–692. [PubMed]
  • van Beek E, Oostendorp-van de Ruit M, van der Wee-Pals L, Bloys H, van de Bent C, Papapoulos S, Löwik C. Effects of experimental conditions on the release of 45calcium from prelabeled fetal mouse long bones. Bone. 1995 Jul;17(1):63–69. [PubMed]
  • de la Mata J, Uy HL, Guise TA, Story B, Boyce BF, Mundy GR, Roodman GD. Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid hormone-related protein in vivo. J Clin Invest. 1995 Jun;95(6):2846–2852. [PMC free article] [PubMed]
  • Rizzoli R, Feyen JH, Grau G, Wohlwend A, Sappino AP, Bonjour JP. Regulation of parathyroid hormone-related protein production in a human lung squamous cell carcinoma line. J Endocrinol. 1994 Nov;143(2):333–341. [PubMed]
  • Horiuchi N, Caulfield MP, Fisher JE, Goldman ME, McKee RL, Reagan JE, Levy JJ, Nutt RF, Rodan SB, Schofield TL, et al. Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro. Science. 1987 Dec 11;238(4833):1566–1568. [PubMed]
  • Hauschka PV, Mavrakos AE, Iafrati MD, Doleman SE, Klagsbrun M. Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. J Biol Chem. 1986 Sep 25;261(27):12665–12674. [PubMed]
  • Pfeilschifter J, Mundy GR. Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones. Proc Natl Acad Sci U S A. 1987 Apr;84(7):2024–2028. [PMC free article] [PubMed]
  • Kiriyama T, Gillespie MT, Glatz JA, Fukumoto S, Moseley JM, Martin TJ. Transforming growth factor beta stimulation of parathyroid hormone-related protein (PTHrP): a paracrine regulator? Mol Cell Endocrinol. 1993 Mar;92(1):55–62. [PubMed]

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