Abstract
Parathyroid hormone-related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer - it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Angiogenic Proteins / biosynthesis
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Angiogenic Proteins / genetics
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Animals
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Antibodies, Neutralizing / immunology
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Antibodies, Neutralizing / therapeutic use
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / genetics
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Breast Neoplasms / pathology
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Breast Neoplasms / therapy
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Cell Adhesion Molecules / biosynthesis
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Cell Adhesion Molecules / genetics
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Disease Progression
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Epithelial Cells / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Mammary Glands, Animal / growth & development
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Mammary Glands, Animal / metabolism
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / pathology*
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Mice
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Mice, Knockout
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Molecular Targeted Therapy
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Neoplasm Metastasis / genetics*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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Neoplasm Proteins / physiology
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Parathyroid Hormone-Related Protein / deficiency
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Parathyroid Hormone-Related Protein / genetics
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Parathyroid Hormone-Related Protein / immunology
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Parathyroid Hormone-Related Protein / physiology*
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Receptors, CXCR4 / biosynthesis
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / physiology
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Xenograft Model Antitumor Assays
Substances
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Angiogenic Proteins
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Antibodies, Neutralizing
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Apoptosis Regulatory Proteins
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CXCR4 protein, mouse
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Cell Adhesion Molecules
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Cell Cycle Proteins
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Neoplasm Proteins
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Parathyroid Hormone-Related Protein
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Receptors, CXCR4