News Note: Scientists identify molecular link between BRCA1 protein levels and obesity
NCI researchers have defined a possible molecular link between breast cancer risk and obesity. New study results show that a protein called C-terminal binding protein (CtBP) acts to control a gene linked to breast cancer risk in rapidly growing cells by monitoring and responding to how the cells use and store energy (metabolic state). The cancer susceptibility gene, BRCA1, performs many functions in the cell, including the regulation of cellular growth and division as well as the repair of DNA or genetic damage. In breast tissue, BRCA1 expression rapidly increases in response to the growth effects caused by estrogen. This study, led by Kevin Gardner, M.D., Ph.D., Laboratory of Receptor Biology and Gene Expression,found that under conditions where there is a metabolic imbalance—available cellular energy is greater than the energy required to carry out cellular functions—the activity of CtBP increases and suppresses the expression of BRCA1.The paper is published in the Nov. 21, 2010 issue of Nature Structural and Molecular Biologywith post-doctoral fellow, Li-Jun Di, Ph.D., as first author.
The scientists demonstrated metabolic imbalance either by manipulating the metabolic state of the human breast cancer cells with drugs, or by deleting expression of the CtBP gene. When they created a cellular energy imbalance, a condition when the cell’s energy stores are very high compared with normal energy usage—much in the way energy imbalance occurs in obesity in humans—the cells produced less BRCA1 type 1 breast cancer susceptibility protein. When they decreased the levels of CtBP or reversed the energy imbalance, they could recover or rescue BRCA1 expression. Past studies have determined that high-fat diets increase the risk and severity of mammary cancer in mice and that calorie restriction has beneficial effects that can reverse this trend. The goal of Gardner and his team is to examine these experimentally induced mammary cancers in combination with available breast-tissue samples from patients in clinical studies to see if increased CtBP activity and lowered BRCA1 expression are important molecular events in breast cancer.