High Surplus Energy Status Blocks Protective Breast Cancer Gene
At the nucleosome, the CtBP1 protein increases the NAD+/NADH ratio and can activate the BRCA1 expression, increase the DNase I hypersensitivity, increase the histone acetylation and reduce the HDAC1 recruitment, removing BRCA1 from its own promoter.
High caloric intake, weight gain, and obesity are associated with increased risk of postmenopausal breast cancer, but little is known about the molecular processes through which these metabolic factors contribute to cancer. Li-Jun Di, Ph.D., and Alfonso Fernandez, Ph.D., postdoctoral fellows working with Kevin Gardner, M.D., Ph.D., in CCR's Laboratory of Receptor Biology and Gene Expression, were part of a research team that recently discovered a link between cellular metabolism and BRCA1, a protein involved in DNA repair as well as the regulation of cell cycle and the expression of many genes. Their findings were published in a recent issue of Nature Structural and Molecular Biology.
Mutations in BRCA1 are known to cause certain types of hereditary breast cancer. Although mutations of BRCA1 are only rarely seen in sporadic forms of breast cancer (cancer that is the result of acquired mutations or cellular changes rather than inherited genomic factors), researchers have long suspected that other types of changes in BRCA1 function could contribute to cancer development. Indeed, studies have shown that nearly 40 percent of sporadic breast cancers have deficiencies in expression of the BRCA1 gene. To gain insight into what might be causing low levels of BRCA1 expression, the researchers used cultured cells to look closely at the region of DNA, called the promoter, that controls expression of this gene. The ability of the promoter to drive expression of the BRCA1 gene is controlled by a small cadre of proteins that bind to this region in a dynamic, interdependent, and sometimes competitive fashion in response to cellular signals.
Experimental manipulation of some of the proteins that act on the BRCA1 promoter revealed an important role for a protein called CtBP. When CtBP is bound to the promoter, it brings along another protein, called HDAC1, that is able to chemically modify histones and other factors at the promoter in a way that makes it less accessible to proteins that promote gene expression. Not surprisingly, the researchers found that when CtBP and HDAC1 were attached to the BRCA1 promoter, less BRCA1 was expressed. In addition, loss of CtBP or inhibition of HDAC1 activity resulted in increased BRCA1 expression.
Interestingly, CtBP is a so-called metabolic sensor, meaning that its ability to bind to chromatin and thus control gene expression is regulated by levels of cellular molecules that reflect the metabolic status of the cell. When the availability of energy is high and there are surplus cellular energy stores, as would be the case with high caloric intake, CtBP is able to more efficiently bind to the BRCA1 promoter and, in cooperation with HDAC1, prevent the proteins that drive BRCA1 expression from accessing the DNA of the BRCA1 promoter. Thus circumstance that result in high surplus energy storage may result in loss of the protective effects of BRCA1 and support the development of tumorigenic processes.
This study suggests a potential mechanism by which an increased metabolic state may lead to breast cancer via reduced expression of BRCA1. Additional studies are needed to determine whether this link is apparent in women who develop breast cancer that is associated with high caloric intake, weight gain, and/or obesity. Understanding the mechanisms by which these factors contribute to breast cancer may facilitate the development of new strategies for breast cancer prevention and treatment.Summary Posted: 11/2010
Di LJ, Fernandez AG, De Siervi A, Longo DL, Gardner K. Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat Struct Mol Biol. November 21, 2010 PubMed Link