1.) We have demonstrated that the BRCA1 promoter and BRCA1 expression is controlled by a complex exchange of transcriptional co-repressors and co-activators including the BRCA1 protein itself. Reports that many cases of sporadic breast cancer show decreased expression of BRCA1 in the absence of BRCA1 mutation and loss of BRCA1 expression is associated with higher grade non-inherited breast cancer thus the goal of defining mechanisms of BRCA1 regulation at the level of transcription is highly significant. This is particularly important in view of recent description of promoter polymorphisms in the BRCA1 promoter that influence lifetime risk of breast cancer. 2.)BRCA1 transcriptional regulation in response to estrogen is driven by the displace or rearrangement of the transcription factor E2F-1 family at the BRCA1 promoter. Regulator exchange involves the cell type specific recruitment of Rb, p130, p107 and BRCA1 which in concert assist in recruiting the histone deacetylase 1 bound (HDAC1) CtBP1 co-repressor molecule in complex with CtIP. This assembly also includes the transcriptional co-activator p300. Following the addition of estrogen, E2F molecules are rearranged and p130, p107, CtBP and HDAC1 are displaced while p300 remains. This occurs with increase acetylation of the centrally positioned nucleosome and an increase in its accessibility to nuclease suggesting a more open chromatin structure at the BRCA1 promoter. 3.) Strikingly the influence of estrogen on the BRCA1 promoter in Breast cancer cells can be mimicked by the addition of the histone deacetylase inhibitor TSA. TSA causes a rapid estrogen-independent increase in BRCA1 transcription while by-passing any change in the assembly of co-activator and co-repressor complexes. The only net change in the promoter is the increase in histone acetylation and promoter accessibility as demonstrate by ChIP for acetylated histones and nuclease sensitivity. 4.) The role of CtBP in the response to metabolic status is well known and these finding suggest the BRCA1 expression may be uniquely responsive to metabolic status. The recent finding that elevated levels of BRCA1 expression controls the level of sirtuin expression suggest that BRCA1 may also be epistatic to factors and pathways that regulate the growth response to cellular energy homeostasis. 5.) The active control of chromatin marks, DNA accessibility and gene expression at the BRCA1 promoter by this metabolic switch provides an important molecular link between caloric intake and tumor suppressor expression in mammary cells. 6.) We now show that CtBP is upregulated in more aggressive forms of breast cancer and high expression predicts worse outcome in breast cancer. 7.) Moreover the list of genes targeted by CtBP classify tumors with worse clinical outcome. 8.) We have developed a drug screen assay to profile potential small molecule inhibitors of CtBP. 9.) We show that calorie restriction decrease the nuclear accumulation of CtBP and improved DNA repair in breast cancer cells. 10.) Analysis of CtBP expression in patient tumor samples demonstrate that higher CtBP expression in tumor epithelial cells correlates with a great than 3 fold higher death rate in breast cancer patients irrespective of race. Notably preliminary data suggests a race-based difference in the levels of CtBP expression and the increased risk of poor outcome, with women of African descent showing a higher risk associated with lower levels of CtBP expression. 11.) Genome-wide profiling of the association of BRCA1 in breast cancer cells indicates that CtBP and BRCA1 form metabolically regulated complexes that influence the expression genes that regulate epithelial phenotypic traits in breast cancer. 12.) Gene expression and epigenetic profiling provides evidence that elevated expression of CtBP contributes to glucose addiction in tumor cells.
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