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Scientists Find Link Between Metabolism and Breast Cancer

Protein associated with obesity and diabetes may play a role (Feb. 5)

A protein associated with conditions of metabolic imbalance, such as diabetes and obesity, may play a role in the development of aggressive forms of breast cancer, according to researchers at the National Cancer Institute. The new findings were published in Nature Communications.

Metabolic imbalance is often caused by elevated carbohydrate intake, which can lead to over-activation of a molecule called C-terminal binding protein (CtBP). This over-activation, in turn, can increase the risk of breast cancer.

“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,” said Kevin Gardner, MD, PhD.

It has been known, primarily through population-based studies, that a strong link exists between obesity and cancer, but the mechanism behind this link has been unclear. A previous study found that CtBP inhibited the expression of a gene associated with breast cancer (BRCA1) at an early age by sensing when the cell was in a high metabolic state. This gene inhibition, in turn, led to the processing of large amounts of carbohydrates in the body.

The findings from this early study suggested that obesity and weight gain may contribute to breast cancer by decreasing the level of expression of the BRCA1 tumor suppressor gene in response to high carbohydrate intake. This explains, in part, why women with hereditary mutations of BRCA1 also experience an increased risk of breast cancer if they gain weight.

The new study expands on this past work. Gardner and his colleagues analyzed prior gene-expression studies to determine whether gene pathways repressed by CtBP were diminished in breast cancer patients who showed more aggressive clinical outcomes.

The investigators began by using genome sequencing to confirm how and where CtBP binds to genes in human breast cancer cells. Next, they compared their analyses with gene-expression studies in which CtBP levels were decreased by RNA interference (a process that inhibits gene expression) or by reduced carbohydrate feeding of the cells.

The researchers found that, under conditions where CtBP levels were decreased, DNA repair increased, and the cells developed stability and growth control. They also determined that gene pathways targeted by CtBP were disrupted in more aggressive breast cancers. Moreover, patients with high levels of CtBP in their tumors had shortened survival.

The investigators also found 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,” Gardner said. “Research should continue to focus on the link between obesity, CtBP, and breast cancer.”

Source: NCI; February 5, 2013.

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