Inherited mutations in the BRCA1 gene, presumably leading to loss of function, confer susceptibility to breast and ovarian neoplasms and are thought to be responsible for approximately 5 percent of all breast cancers. It has been suggested that mechanisms, other than mutations, may also be involved in the suppression of BRCA1 gene expression in breast cancers. For example, a report of reduced BRCA1 mRNA expression in sporadic breast cancers, suggests a broader role of this tumor suppressor gene in breast cancers than previously appreciated. The decrease of BRCA1 mRNA in breast cancer may be a result of transcriptional repression. Therefore, we chose to study the BRCA1 transcriptional promoters, which we have isolated. We have demonstrated BRCA1 promoters activity utilizing reporter gene assays. Our preliminary studies suggest BRCA1 promoters activity is increased by signals inducing proliferation like estrogen and also by the transcription factor B-Myb. We have initiated a detailed mutational analysis of the BRCA1 promoters and mapped sites potentially involved in negative and positive regulation of transcription. We propose to characterize in detail, the mechanism of promoters transcriptional activity and responses, including identification of cis- and transactivating factors which mediate them. Understanding the mechanisms involved in the regulation of BRCA1 transcription and the influence of various factors, may provide clues regarding the manner in which BRCA1 expression is dysregulated, leading to the development of a neoplastic phenotype. Characterization of the transcriptional mechanisms which regulate BRCA1 expression may provide specific targets for therapeutic drugs in the treatment of breast cancers.
| Thakur, S; Croce, C M (1999) Positive regulation of the BRCA1 promoter. J Biol Chem 274:8837-43 |
