A molecular mechanism has been discovered that explains why excess calories are associated with increased breast cancer risk.
The epidemiology has been clear for decades—overweight and obese women have a greater risk of breast cancer—but molecular biologists have been unable to explain how the link works until now.
In the Nov. 21 online issue of Nature Structural & Molecular Biology, NCI researchers report that a transcriptional co-repressor protein, called C-terminal binding protein (CtBP), monitors the amount of energy a cell has and uses that information to regulate transcription of the BRCA1 gene. Too much stored energy means less BRCA1 activity and less DNA repair.
“It is really the first molecular link where we actually can say it is this molecule, under this process,” said senior author Kevin Gardner MD, PhD, of the Laboratory of Receptor Biology & Gene Expression.
When a cell has excess energy, the ratio of two metabolic co-enzymes, NAD+/NADH, drops. CtBP senses this shift by binding to NADH and becomes active, shutting down transcription of BRCA1. That cripples the cell's DNA repair system, much like mutations in BRCA1 might.
And with experts estimating that there can be as many as 100,000 spontaneous DNA changes in every cell every day, a breakdown in the DNA repair system is serious trouble.
In fact, Dr. Gardner refers to the excess calorie problem as a “perfect storm.” At the same time CtBP shuts down BRCA1 transcription, fat cells, which have aromatase enzymes, increase the amount of circulating estrogen.
The hormone, in turn, stimulates cell proliferation in hormone responsive tissues, such as the breast and ovary. That means that as cells are undergoing the error-prone process of replication, their ability to repair those errors drops. And—voila!—cancer risk jumps in hormone sensitive tissue.
Unfortunately, understanding the molecular link doesn't change the basic facts of the matter: We still need to control our eating—or get more exercise to compensate for the extra calories—if we want to keep our cancer risk as low as possible.
The good news, though, is that data in the Dec. 2 issue of the New England Journal of Medicine indicate that it is not necessary to be super skinny to keep our cancer—and all-cause—mortality risk down.
In fact, people who had a body mass index between 20.0 and 24.9 had the lowest all-cause mortality, and although there was a numerical drop in cancer deaths with a body mass index below that, the decline was not statistically significant.