Abstract
Parathyroid hormone-related protein (PTHrP) is required for mammary gland development and promotes the growth of breast cancer metastases within bone. However, there are conflicting reports of the prognostic significance of its expression in primary breast cancers. To study the role of PTHrP in early breast cancer, the effect of conditional deletion of PTHrP was examined in the context of neu-induced mammary tumorigenesis. Loss of PTHrP resulted in a higher tumor incidence. Transcriptional profiling of the tumors revealed that PTHrP influenced genes relevant to heterotypic cell signaling, including regulators of monocyte recruitment. Immunohistochemical analysis of human breast cancers revealed that PTHrP expression was associated with both HER-2/neu expression and macrophage infiltration in preinvasive ductal carcinoma in situ. The gene expression signature associated with loss of PTHrP expression in vivo correlated with poorer outcome in human breast cancer. Together, these data indicate that loss of PTHrP accelerates mammary tumorigenesis possibly by a non-cell-autonomous tumor suppressor pathway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / immunology
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Antigens, Differentiation, Myelomonocytic / immunology
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Breast Neoplasms / genetics
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Breast Neoplasms / immunology
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Carcinoma, Intraductal, Noninfiltrating / genetics
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Carcinoma, Intraductal, Noninfiltrating / immunology
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Carcinoma, Intraductal, Noninfiltrating / metabolism*
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Carcinoma, Intraductal, Noninfiltrating / pathology
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Female
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Gene Deletion
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Gene Expression Profiling
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Male
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / immunology
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / pathology
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Mammary Tumor Virus, Mouse / genetics
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Monocytes / immunology*
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Monocytes / pathology
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Parathyroid Hormone-Related Protein / biosynthesis*
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Parathyroid Hormone-Related Protein / deficiency
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Parathyroid Hormone-Related Protein / genetics
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Receptor, ErbB-2 / biosynthesis
Substances
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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CD68 antigen, human
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Parathyroid Hormone-Related Protein
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Receptor, ErbB-2