pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 multimolecular complexes mediate the transcription of estrogen receptor-alpha in breast cancer.
The estrogen receptor-alpha (ER) plays a crucial role in normal breast development and is also linked to development and progression of mammary carcinoma. The transcriptional repression of ER-alpha gene in breast cancer is an area of active investigation with potential clinical significance. However, the molecular mechanisms that regulate the ER-alpha gene expression are not fully understood. Here we show a new molecular mechanism of ER-alpha gene inactivation mediated by pRb2/p130 in ER-negative breast cancer cells. We investigated in vivo occupancy of ER-alpha promoter by pRb2/p130-E2F4/5-HDAC1-SUV39 H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 complexes, and provided a link between pRb2/p130 and chromatin-modifying enzymes in the regulation of ER-alpha transcription in a physiological setting. These findings suggest that pRb2/p130-multimolecular complexes can be key elements in the regulation of ER-alpha gene expression and may be viewed as promising targets for the development of novel therapeutic strategies in the treatment of breast cancer, especially for those tumors that are ER negative.
Macaluso
Marcella
M
Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA, USA.
Cinti
Caterina
C
Russo
Giuseppe
G
Russo
Antonio
A
Giordano
Antonio
A
D000107:Acetylation; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011506:Proteins; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D002843:Chromatin; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D050700:E2F5 Transcription Factor; C092558:E2F5 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006657:Histones; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; C493837:RBL2 protein, human; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D050717:Retinoblastoma-Like Protein p130; D015534:Trans-Activators; D014157:Transcription Factors; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases