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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010847-07
Application #
8763250
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$911,755
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
De Luca, Paola; Dalton, Guillermo N; Scalise, Georgina D et al. (2016) CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs. Oncotarget 7:18798-811
Zalazar, Florencia; De Luca, Paola; Gardner, Kevin et al. (2015) Low doses of CPS49 and flavopiridol combination as potential treatment for advanced prostate cancer. Curr Pharm Biotechnol 16:553-63
Moiola, Cristian P; De Luca, Paola; Zalazar, Florencia et al. (2014) Prostate tumor growth is impaired by CtBP1 depletion in high-fat diet-fed mice. Clin Cancer Res 20:4086-95
Byun, Jung S; Gardner, Kevin (2013) C-Terminal Binding Protein: A Molecular Link between Metabolic Imbalance and Epigenetic Regulation in Breast Cancer. Int J Cell Biol 2013:647975
Byun, Jung S; Gardner, Kevin (2013) Wounds that will not heal: pervasive cellular reprogramming in cancer. Am J Pathol 182:1055-64
Alsarraj, Jude; Faraji, Farhoud; Geiger, Thomas R et al. (2013) BRD4 short isoform interacts with RRP1B, SIPA1 and components of the LINC complex at the inner face of the nuclear membrane. PLoS One 8:e80746
Di, Li-Jun; Byun, Jung S; Wong, Madeline M et al. (2013) Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun 4:1449
De Luca, P; Moiola, C P; Zalazar, F et al. (2013) BRCA1 and p53 regulate critical prostate cancer pathways. Prostate Cancer Prostatic Dis 16:233-8
Moiola, Cristian; De Luca, Paola; Cotignola, Javier et al. (2012) Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription. Cell Physiol Biochem 30:596-608
Wakano, Clay; Byun, Jung S; Di, Li-Jun et al. (2012) The dual lives of bidirectional promoters. Biochim Biophys Acta 1819:688-93

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