Abstract
The presence of hypoxia and fibrosis within the primary tumor are two major risk factors for metastasis of human breast cancer. In this study, we demonstrate that hypoxia-inducible factor 1 activates the transcription of genes encoding collagen prolyl hydroxylases that are critical for collagen deposition by breast cancer cells. We show that expression of collagen prolyl hydroxylases promotes cancer cell alignment along collagen fibers, resulting in enhanced invasion and metastasis to lymph nodes and lungs. Finally, we establish the prognostic significance of collagen prolyl hydroxylase mRNA expression in human breast cancer biopsies and show that ethyl 3,4-dihydroxybenzoate, a prolyl hydroxylase inhibitor, decreases tumor fibrosis and metastasis in a mouse model of breast cancer.
©2013 AACR.
Publication types
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Research Support, N.I.H., Extramural
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Retracted Publication
MeSH terms
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Animals
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Breast Neoplasms / drug therapy
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Breast Neoplasms / enzymology*
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology*
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Cell Hypoxia / physiology
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Cell Line, Tumor
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Collagen / metabolism
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Female
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Gene Knockdown Techniques
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Humans
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Hydroxybenzoates / pharmacology
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Procollagen-Proline Dioxygenase / antagonists & inhibitors
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Procollagen-Proline Dioxygenase / biosynthesis
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Procollagen-Proline Dioxygenase / genetics
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Procollagen-Proline Dioxygenase / metabolism*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
Substances
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HIF1A protein, human
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Hydroxybenzoates
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Hypoxia-Inducible Factor 1, alpha Subunit
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RNA, Messenger
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ethyl protocatechuate
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Collagen
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P4HA1 protein, human
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Procollagen-Proline Dioxygenase