Overexpression of parathyroid hormone-related protein causes hypercalcemia but not bone metastases in a murine model of mammary tumorigenesis

John J. Wysolmerski, Pamela R. Dann, Edward Zelazny, Maureen E. Dunbar, Karl L. Insogna, Theresa Guise, Archibald S. Perkins

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Several lines of evidence suggest that production of parathyroid hormone-related protein (PTHrP) by breast cancer cells contributes to the formation of bone metastases. However, it is not clear if PTHrP promotes access of cancer cells to the skeleton or if it simply promotes bone resorption around cells already within bone. To study the effects of PTHrP on the development of bone metastases, we treated mice overexpressing PTHrP in their mammary glands (K14-PTHrP transgenic mice) with 9,10-dimethyl-1,2-benz-anthracene (DMBA), a known mammary carcinogen. After DMBA treatment, K14-PTHrP mice showed a higher incidence of tumor formation and a shorter latency to tumor formation than wild-type littermates. Transgenic tumors expressed the K14-PTHrP transgene and secreted excess amounts of PTHrP. In response, tumor-bearing transgenic mice became hypercalcemic and had elevated circulating levels of PTHrP. Despite the development of visceral metastases, neither transgenic mice nor wild-type controls developed bone metastases. This was true even if tumor cells were introduced into the arterial circulation of immunodeficient mice. Our results are consistent with the emerging notion that the ability of breast cancer cells to produce PTHrP in response to cues from the bone microenvironment may be more important to the development of skeletal metastases than the production of PTHrP by cells within the primary breast cancer.

Original languageEnglish (US)
Pages (from-to)1164-1170
Number of pages7
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume17
Issue number7
StatePublished - 2002
Externally publishedYes

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Parathyroid Hormone-Related Protein
Hypercalcemia
Carcinogenesis
Breast
Neoplasm Metastasis
Bone and Bones
Transgenic Mice
Neoplasms
Breast Neoplasms
Aptitude
Bone Development
Human Mammary Glands
Bone Resorption
Transgenes
Osteogenesis
Skeleton
Carcinogens
Cues

Keywords

  • Bone metastases
  • Breast cancer
  • Chemical carcinogen
  • Parathyroid hormone-related protein
  • Transgenic mice

ASJC Scopus subject areas

  • Surgery

Cite this

Overexpression of parathyroid hormone-related protein causes hypercalcemia but not bone metastases in a murine model of mammary tumorigenesis. / Wysolmerski, John J.; Dann, Pamela R.; Zelazny, Edward; Dunbar, Maureen E.; Insogna, Karl L.; Guise, Theresa; Perkins, Archibald S.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 17, No. 7, 2002, p. 1164-1170.

Research output: Contribution to journalArticle

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