Dr. Deng and colleagues were interested in investigating the relationship among BRCA1, SIRT1 and Survivin. SIRT1 is a protein and histone deacetylase involved in numerous critical cell processes including metabolism, DNA repair and programmed cell death, known as apoptosis. Although SIRT1 has been implicated in tumorigenesis, no concrete role in cancer initiation or progression has been identified. Survivin is an apoptosis inhibitor that is dramatically elevated in many types of tumors. Research has suggested that Survivin may serve to maintain the tumor and promote growth.
The researchers found that BRCA1 functioned as a tumor suppressor by maintaining SIRT1 expression, which in turn inhibited Survivin expression. When BRCA1 was not functioning properly, SIRT levels decreased and Survivin levels increased, allowing BRCA1-deficient cells to overcome apoptosis and undergo malignant transformation.
They went on to show that the compound resveratrol strongly inhibited BRCA1-mutant tumor growth in cultured cells and animal models. Resveratrol is an important constituent of traditional Japanese and Chinese medicine that has recently been shown to inhibit some types of cancer by inducing apoptosis with very little associated toxicity. In the current paper, resveratrol enhanced SIRT1 activity, this leading to reduced Survivin expression and subsequent apoptosis of BRCA1 deficient cancer cells.
These findings identify SIRT1 and Survivin as downstream mediators of BRCA1-regulated tumor suppression and identify resveratrol as a potent inhibitor of BRCA1-mutant cancer cells. "Resveratrol may serve as an excellent compound for targeted therapy for BRCA1 associated breast cancers," says Dr. Deng.
If resveratrol really works in the way described there is a substantial chance that resveratrol might decrease the odds of getting breast cancer in the first place - especially among women who have the BRCA1 mutation that increases the odds of getting breast cancer. Resveratrol appears to substitute for properly formed BRCA1 and enhance SIRT1 which lowers the expression of Survivin. Survivin helps keep cells alive. So less Survivin causes more cancer cells to commit suicide.
Germline mutations of BRCA1 predispose women to breast and ovarian cancers. However, the downstream mediators of BRCA1 function in tumor suppression remain elusive. We found that human BRCA1-associated breast cancers have lower levels of SIRT1 than their normal controls. We further demonstrated that mammary tumors from Brca1 mutant mice have low levels of Sirt1 and high levels of Survivin, which is reversed by induced expression of Brca1. BRCA1 binds to the SIRT1 promoter and increases SIRT1 expression, which in turn inhibits Survivin by changing the epigenetic modification of histone H3. Absence of SIRT1 blocks the regulation of Survivin by BRCA1. Furthermore, we demonstrated that activation of Sirt1 and inhibition of Survivin expression by resveratrol elicit a more profound inhibitory effect on Brca1 mutant cancer cells than on Brca1-wild-type cancer cells both in vitro and in vivo. These findings suggest that resveratrol treatment serves as an excellent strategy for targeted therapy for BRCA1-associated breast cancer.
I periodically mull over the possibility of taking resveratrol for its various reported benefits. Still haven't crossed over to taking it yet. I expect I'll take it when I get older and my risk of cancer goes up.
|Share |||Randall Parker, 2008 October 31 04:42 AM Aging Diet Resveratrol|