Abstract
The ErbB2 (Neu) receptor tyrosine kinase is frequently overexpressed in human breast cancers, and this phenotype correlates with a poor clinical prognosis. We examined the effects of the mammalian target of rapamycin inhibitor, rapamycin, on mammary tumorigenesis in transgenic mice bearing an activated ErbB2 (NeuYD) transgene in the absence or presence of a second transgene encoding vascular endothelial growth factor (VEGF). Treatment of NeuYD or NeuYD x VEGF mice with rapamycin dramatically inhibited tumor growth accompanied by a marked decrease in tumor vascularization. Two key events that may underlie the antitumor activity of rapamycin were decreased expression of ErbB3 and inhibition of hypoxia-inducible factor-1-dependent responses to hypoxic stress. Rapamycin exposure caused only a modest inhibition of the proliferation of tumor-derived cell lines in standard monolayer cultures, but dramatically inhibited the growth of the same cells in three-dimensional cultures, due in part to the induction of apoptotic cell death. These studies underscore the therapeutic potential of mammalian target of rapamycin inhibitors in ErbB2-positive breast cancers and indicate that, relative to monolayer cultures, three-dimensional cell cultures are more predictive in vitro models for studies of the antitumor mechanisms of rapamycin and related compounds.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Breast Neoplasms / blood supply
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Cell Proliferation / drug effects
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DNA-Binding Proteins / biosynthesis
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Female
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Male
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Mammary Neoplasms, Experimental / blood supply
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Mammary Neoplasms, Experimental / drug therapy*
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Mammary Neoplasms, Experimental / genetics
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Mice
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Mice, Transgenic
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Nuclear Proteins / biosynthesis
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Phosphorylation
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Protein Kinases / metabolism
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Receptor, ErbB-2 / biosynthesis*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-3 / biosynthesis
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Sirolimus / pharmacology*
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Spheroids, Cellular
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TOR Serine-Threonine Kinases
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Transcription Factors / biosynthesis
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor A / genetics
Substances
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DNA-Binding Proteins
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Receptor, ErbB-2
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Receptor, ErbB-3
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TOR Serine-Threonine Kinases
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Sirolimus