MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells.
Overexpression of the oncoprotein MDM2, a negative feedback regulator of p53, is often observed in breast cancer tissue and cell lines, particularly in those which express estrogen receptor alpha (ERalpha). In this study, we report a novel function of MDM2, i.e., as a positive regulator of ERalpha. This function does not involve p53. MDM2 overexpressing clones derived from the breast cancer cell line, MCF-7 cells, showed a remarkable growth advantage only in estradiol supplemented conditions, and this profile coincided with increased transcriptional activity of ERalpha in these cells. Though p53 has been reported to be an inhibitor of ERalpha function, p53 protein in MDM2 overexpressing clones was more abundant than in the parental cells. When ERalpha was exogenously expressed in p53-null cells, its activity was enhanced by coexpression of MDM2. Mammalian two-hybrid assays and GST pull-down assays indicated that MDM2 could interact with ERalpha. These results indicate that MDM2 is a direct activator of ERalpha function, and suggest such a role for MDM2 in ERalpha-positive breast cancer.
Saji
S
S
Division of Endocrinology, Laboratory of Cancer Diagnosis and Therapy, Saitama Cancer Center Research Institute, 818 Komuro, Saitama, Ina-machi, Kitaadachi-gun, 362-0806, Japan.
Okumura
N
N
Eguchi
H
H
Nakashima
S
S
Suzuki
A
A
Toi
M
M
Nozawa
Y
Y
Saji
S
S
Hayashi
S
S
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009687:Nuclear Proteins; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D011960:Receptors, Estrogen / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase