A Transcriptional Co-Repressor Protein Links Obesity to Breast Cancer Risk

Weight gain and high-carbohydrate diets increase risk of developing breast cancer due to the activity of the transcriptional co-repressor protein CtBP (C-terminal binding protein).

The CtBP protein family has gained wide scientific interest due to findings that identified its critical role in animal development and oncogenesis. These multifunctional proteins predominantly function as transcriptional co-repressors in the nucleus by recruiting various histone-modifying enzymes such as histone deacetylases, histone methylases, and a histone demethylase. They also perform several diverse cytosolic functions such as Golgi maintenance and in central nervous system synapses.

Investigators at the [US] National Cancer Institute (Bethesda, MD, USA) used advanced genomic techniques to profile levels of CtBP in breast cancer cells. They reported in the February 5, 2013, online edition of the journal Nature Communications that elevated levels of CtBP in patient tumors predicted shorter survival time.

A high level of CtBP was found to drive epithelial-to-mesenchymal transition, stem cell pathways, and genome instability. Depletion of CtBP or caloric restriction reversed gene repression and increased DNA repair. Several members of the CtBP-targeted gene network were selectively downregulated in aggressive breast cancer subtypes. This group included the BRCA1 tumor suppressor gene. Both CtBP promoter targeting and gene repression could be reversed by small molecule inhibition.

“Our new work suggests that targeting CtBP may provide a way of treating breast cancer and possibly preventing breast cancer,” said senior author Dr. Kevin Gardner, head of the transcription regulation section at the [US] National Cancer Institute. “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. Research should continue to focus on the link between obesity, CtBP, and breast cancer. This will require more population-based studies and multidisciplinary teams of scientist to investigate these links.”

Related Links:
National Cancer Institute