Abstract
In cultured neuroblastoma cells, hypoxia induces a dedifferentiated phenotype. We tested whether hypoxia-induced dedifferentiation also occurs in vivo in mammary ductal carcinoma in situ with its well-defined lesions and distinct areas of necrosis. Ductal carcinoma in situ cells surrounding the central necrosis have high hypoxia inducible factor-1alpha protein levels, down-regulated estrogen receptor-alpha, and increased expression of the epithelial breast stem cell marker cytokeratin 19; lose their polarization; and acquire an increased nucleus/cytoplasm ratio, hallmarks of poor architectural and cellular differentiation. The hypoxia-induced changes were confirmed in cultured breast cancer cells. We propose that hypoxia-induced dedifferentiation is a mechanism that promotes tumor progression in breast cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Carcinoma in Situ / genetics
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Carcinoma in Situ / metabolism
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Carcinoma in Situ / pathology*
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Carcinoma, Ductal, Breast / genetics
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Carcinoma, Ductal, Breast / metabolism
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Carcinoma, Ductal, Breast / pathology*
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Cell Differentiation / physiology
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Cell Hypoxia / physiology
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Down-Regulation
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Estrogen Receptor alpha
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Gene Expression Regulation, Neoplastic
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Keratins / biosynthesis
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Keratins / genetics
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Necrosis
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Receptors, Estrogen / biosynthesis
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Receptors, Estrogen / genetics
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Tumor Cells, Cultured
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Up-Regulation
Substances
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Estrogen Receptor alpha
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Receptors, Estrogen
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Transcription Factors
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Keratins