Findings of a new study reported by researchers at the National Cancer Institute suggest that targeting C-terminal binding protein (CtBP) may one day be a way of treating "and possibly preventing breast cancer," according to Kevin Gardner, MD, PhD, lead investigator of the study, published last week in Nature Communications.
Metabolic imbalance, associated with conditions such as diabetes and obesity, is often caused by elevated carbohydrate intake, which can lead to over-activation of CtBP, which in turn can increase the risk of breast cancer, explained Gardner, head of NCI's Transcription Regulation Section, Genetics Branch.
Findings of a previous study conceived and conducted in Gardner's laboratory suggested that obesity and weight gain may contribute to breast cancer by decreasing the level of the BRCA1 tumor suppressor gene expression in response to high carbohydrate intake. This explains, in part, why women who have hereditary mutations of BRCA1 also experience an increased risk of breast cancer if they gain weight. BRCA1 mutations have become identified as strong predictors of breast and ovarian cancer -- so strong that the gene's DNA sequence has been the subject of contentious litigation about whether the gene and diagnostic tests to detect it can be patented.
The new study expands upon Gardner's past work. The investigators analyzed prior gene expression studies to determine if gene pathways repressed by CtBP were diminished in breast cancer patients who experienced more aggressive clinical outcomes. Starting with human breast cancer cells in the laboratory, Gardner's team measured the association of CtBP and the genes it bound to in order to regulate expression. The researchers combined this approach with genome sequencing to confirm how and where CtBP bound to genes associated with breast cancer.
Next, they integrated analyses with gene expression studies in cells in which they decreased levels of CtBP by RNA interference, or by lowering carbohydrate feeding of the cells. They found that under conditions where they decreased the levels of CtBP, DNA repair increased and the cells developed stability and growth control. Gene pathways targeted by CtBP were also disrupted in more aggressive breast cancers. Moreover, patients with high levels of CtBP in their tumors had shortened survival. And they showed that a small molecular inhibitor previously shown to bind to CtBP was able to reverse the gene-repressive effects of CtBP in breast cancer cells even under conditions of high carbohydrate feeding.
Our new work suggests that targeting CtBP may provide a way of treating breast cancer and possibly preventing breast cancer. Research should continue to focus on the link between obesity, CtBP and breast cancer. This will require more population-based studies and multi-disciplinary teams of scientist to investigate these links.
Modifying diet and maintaining a healthy diet, combined with developing pharmacological ways of lessening CtBP activity may one day lead to a way to break the link between cancer and obesity.
Gardner's enthusiasm for his work is displayed in an NIH videocast of a lecture he gave in 2004 titled "How the Genome Comes Alive: Novel Approaches for Studying Transcriptional Regulation in Mammalian Cells."
- Di LJ, Byun JS, Wong MM, Wakano C, Taylor T, et al. Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nature Communications. Feb 5;4:1449. doi: 10.1038/ncomms2438.