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

Theresa A. Guise, Juan Juan Yin, Suzanne D. Taylor, Yoshinari Kumagai, Mark Dallas, Brendan F. Boyce, Toshiyuki Yoneda, Gregory R. Mundy

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1544-1549
Number of pages6
JournalJournal of Clinical Investigation
Volume98
Issue number7
DOIs
StatePublished - Oct 1 1996

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Parathyroid Hormone-Related Protein
Osteolysis
Breast Neoplasms
Bone and Bones
Neoplasm Metastasis
Neoplasms
Hypercalcemia
Cell Line
Blood Proteins
Immunoglobulin G
Antibodies
Bone Development
Osteoclasts
Neutralizing Antibodies
Skeleton
Causality
Femur

Keywords

  • bone metastases
  • hypercalcemia
  • malignancy
  • osteoclast
  • parathyroid hormone-related protein

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. / Guise, Theresa A.; Yin, Juan Juan; Taylor, Suzanne D.; Kumagai, Yoshinari; Dallas, Mark; Boyce, Brendan F.; Yoneda, Toshiyuki; Mundy, Gregory R.

In: Journal of Clinical Investigation, Vol. 98, No. 7, 01.10.1996, p. 1544-1549.

Research output: Contribution to journalArticle

Guise, Theresa A. ; Yin, Juan Juan ; Taylor, Suzanne D. ; Kumagai, Yoshinari ; Dallas, Mark ; Boyce, Brendan F. ; Yoneda, Toshiyuki ; Mundy, Gregory R. / Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. In: Journal of Clinical Investigation. 1996 ; Vol. 98, No. 7. pp. 1544-1549.
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AU - Mundy, Gregory R.

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