Overexpression of Parathyroid Hormone-Related Protein Causes Hypercalcemia but Not Bone Metastases in a Murine Model of Mammary Tumorigenesis

Authors

  • John J. Wysolmerski M.D.,

    Corresponding author
    1. Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
    • Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, FMP 102, 333 Cedar Street, New Haven, CT 06520, USA
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  • Pamela R. Dann,

    1. Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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  • Edward Zelazny,

    1. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
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  • Maureen E. Dunbar,

    1. Department of Biology, Pennsylvania State University, Berks Campus, Reading, Pennsylvania, USA
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  • Karl L. Insogna,

    1. Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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  • Theresa A. Guise,

    1. Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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  • Archibald S. Perkins

    1. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
    2. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, USA
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  • The authors have no conflict of interest.

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.

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