Abstract
Several oncoproteins or tumor suppressor gene products have been indicated to be of value as predictors of the de novo resistance to cytotoxic agents. In this study, we have investigated the role of MDM2 (murine double minutes) overexpression in doxorubicin resistance of breast cancer. Immunocytochemical analysis demonstrated that MDM2-positive tumors, even with p53-negative phenotype, were significantly more resistant to doxorubicin treatment compared to MDM2-negative tumors. An in vitro experimental model using stable mdm2-transfected MCF-7 cells carrying wild-type p53 confirmed that the cells become approximately 3-fold more resistant to doxorubicin as a result of MDM2 overexpression, and the wild-type p53 function, such as the induction of p21Waf1 following DNA damage, was significantly suppressed. MDM2 overexpression is suggested to be a novel marker for predicting lack of response to doxorubicin treatment in breast cancer patients.
MeSH terms
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Antibiotics, Antineoplastic / pharmacology*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm
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Female
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Gene Expression
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Humans
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Immunohistochemistry
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Nuclear Proteins*
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-mdm2
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / biosynthesis
Substances
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Antibiotics, Antineoplastic
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Neoplasm Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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Doxorubicin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2