Transcription factor can stifle breast cancer suppressing gene

A transcription factor known as Snail1 can act as a “molecular bypass” that diminishes the natural tumor suppressing action of a gene called p53 in breast cancer patients, a group of scientists led by the University of Michigan and China Pharmaceutical University have found.

In a large cohort of breast cancer patients, the researchers found those with high expression of Snail1 and normal p53 genes were more likely to have relapses of their cancer, to have their cancer metastasize and to have a lower overall survival rate, according to a study published October 17 in Nature Cell Biology.

The researchers made the findings while trying to understand the role Snail1 played in breast cancer progression in patients with both normal and mutated copies of the p53 gene. The p53 gene is sometimes called a “guardian of the genome” because mutations in it are associated with the development of many human cancers. In breast cancer, however, most patients do not have mutations in their p53 genes and the manner in which tumor cells bypass its protective effects have remained unknown.

While examining patient outcome data, the scientists noticed the correlation between high Snail1 levels and accelerated disease progression in patients with normal p53 genes. Follow-up studies in a mouse model of human breast cancer showed that animals engineered to lack Snail1 developed both fewer and smaller tumors than their counterparts. Importantly, deleting Snail1 did not adversely affect mammary gland development, the researchers found.

“Most breast cancer patients have a normal p53 gene — only about 25 percent don’t. This research points toward the possibility that Snail1-p53 interactions might be modulated for therapeutic benefit in breast cancer and other types of cancer,” says study co-senior author Stephen J. Weiss, M.D., a professor of internal medicine and oncology at the U-M Medical School, research professor U-M Life Sciences Institute, where his lab is located, and associate director for basic science research at the U-M Comprehensive Cancer Center.