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The 85-kb breast cancer-associated gene BRCA1 is an established tumor suppressor gene, but its regulation is poorly understood. We demonstrate by gene conformation analysis in both human cell lines and mouse mammary tissue that gene loops are imposed on BRCA1 between the promoter, introns, and terminator region. Significantly, association between the BRCA1 promoter and terminator regions change upon estrogen stimulation and during lactational development. Loop formation is transcription-dependent, suggesting that transcriptional elongation plays an active role in BRCA1 loop formation. We show that the BRCA1 terminator region can suppress estrogen-induced transcription and so may regulate BRCA1 expression. Significantly, BRCA1 promoter and terminator interactions vary in different breast cancer cell lines, indicating that defects in BRCA1 chromatin structure may contribute to dysregulated expression of BRCA1 seen in breast tumors.

Original publication

DOI

10.1073/pnas.0801048105

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

01/04/2008

Volume

105

Pages

5160 - 5165

Keywords

Animals, BRCA1 Protein, Breast, Breast Neoplasms, Cell Line, Tumor, Chromatin, DNA, Estrogens, Female, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Inbred C57BL, Models, Molecular, Nucleic Acid Conformation, Promoter Regions, Genetic, Terminator Regions, Genetic, Transcription, Genetic