One of the molecular players in breast cancer arising from an inherited mutation has a surprising role in squelching tumors, researchers report in the Oct. 10 Molecular Cell. 

In some types of cancer cells, researchers have shown that a gene called SIRT1 acts to keep cells alive longer, which leads to more tumor growth. But SIRT1 actually inhibits tumor growth in breast cancers caused by specific mutations in the BRCA1 gene, the new research shows. 

People who carry a mutated form of the gene BRCA1 are about three to seven times more likely to develop breast cancer over the course of their lives than women who carry a healthy version. Although researchers have known about the risks of BRCA1 mutations since 1994, it is unclear exactly how this mutation leads to cancer. To work out the molecules involved, researchers investigated a gene called SIRT1, which belongs to a gene family known to play roles in heart health, energy production and aging.

“SIRT1 has quite a long history in aging and metabolism,” says senior author Chu-Xia Deng of the National Institutes of Health in Bethesda, Md. 

SIRT1’s role in cancer, though, is muddled. SIRT1 was originally thought to be an oncogene that caused tumors to grow larger.

In the case of BRCA1-inherited breast cancer, however, Deng and his team found the opposite — more of the protein made by SIRT1 led to fewer tumors in mice and human cancer cells.

First the team showed that the protein encoded by BRCA1 attaches to a region of DNA that controls levels of SIRT1. Next, the researchers measured amounts of SIRT1 in tumors caused by a BRCA1 mutation, and compared it to amounts of SIRT1 in non-BRCA1-related tumors. Surprisingly, BRCA1-related breast cancer tumors in both human cell lines and mice had lower levels of SIRT1 than tumors that were not BRCA1-related, indicating that SIRT1 might be suppressing tumor formation. This means that for BRCA1-related breast cancer in particular, more SIRT1 means fewer tumors.  

Next the team increased the levels of SIRT1 in BRCA1-associated cancers in mice, and saw that the mice grew fewer tumors than controls. The scientists conclude that the higher level of SIRT1 was able to slow tumor growth in cancer caused by BRCA1 mutations. 

These results were surprising in light of previous reports showing that high levels of SIRT1 enhance growth of other types of tumors. It now appears that SIRT1 can enhance or inhibit tumor growth — it all depends on the context, says Deng. 

Leonard Guarente of MIT, who was the first to discover that the worm version of SIRT1 regulates longevity in worms, calls this study highly significant because it uncovers a new mechanism for BRCA1-associated breast cancer.

The researchers also found that a red wine chemical called resveratrol, recently touted as a powerful antiaging compound, was effective in combating BRCA1-associated tumor formation specifically.

How resveratrol is able to do this is unclear. “The work in this case is that SIRT1 has an antitumor effect, and this paper provides mechanistic insights into that,” comments Pere Puigserver, a Harvard biologist who studies SIRT1. But the resveratrol data should be taken with caution, he notes. While this new research clearly shows the direct relationship between BRCA1 and SIRT1, the direct link between resveratrol and SIRT1 is more difficult to demonstrate.

Nonetheless, molecular details of BRCA1-related breast cancer are emerging, and this new data places SIRT1 squarely inside the complex web of molecules that impact tumor growth. 

“The tide has begun to turn on how SIRT1 relates to cancer,” says Guarente.

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Found in: Genes & Cells