A Red Flag For Lethal Prostate Cancer

In an article published in the Oct. 10 issue of Nature, U-M scientist Arul M. Chinnaiyan, M.D., Ph.D., and his research team used advanced DNA microarray technology to show that EZH2 expression was at "the top of the list" of 55 genes found to be more active in metastatic prostate cancer than in localized prostate cancer. This is the first study linking EZH2 to solid tumors, according to Chinnaiyan.

When the EZH2 gene is active, the cell uses its coded instructions to produce EZH2 protein. U-M scientists believe a future diagnostic test for high levels of this protein could serve as a red flag for physicians and help save the lives of men with the most dangerous form of the disease.

"We found the greatest EZH2 overexpression in metastatic prostate cancer tissue. At this point, it's unclear whether the gene plays a role in cancer's development or is simply an indicator of lethal progression," says Chinnaiyan, an assistant professor of pathology and urology in the U-M Medical School.

EZH2 is one of several related proteins that control a cell's genetic memory and interfere with transcription – the process cells use to transcribe or copy their genetic code. According to Chinnaiyan, it is similar to a gene recently shown to shut down transcription in fruit flies.

If additional research and human clinical trials confirm the U-M results, a test for EZH2 protein could, for the first time, allow physicians to identify accurately those men who need immediate, aggressive treatment to prevent the cancer from spreading outside the prostate. Once prostate cancer metastasizes, or spreads, to other organs, it is usually incurable.

"Over the past 50 years, there has been no significant improvement in clinical outcome for men diagnosed with advanced prostate cancer and no way to tell ahead of time which cancers will spread and which cancers will remain localized," says Mark A. Rubin, M.D., a former U-M faculty member, who is now an associate professor of pathology at Brigham and Women's Hospital and director of the Dana Farber Harvard Cancer Center Tissue Microarray Core. "It is exciting to think that we may have finally found something to help the 30,000 men who die every year from metastatic prostate cancer."

To validate their DNA microarray results, U-M researchers analyzed levels of EZH2 protein in more than 1,000 prostate tissue samples. They included normal prostate tissue, tissue with non-malignant cell changes, and tissue with localized and advanced cancer. Four hundred of these tissue samples were donated by U-M Health System patients who died from hormone-refractory metastatic prostate cancer.

"We never would have discovered this molecule without gene expression tumor profiles from these patients who donated their tissue," Rubin says. "We owe them a real debt of gratitude. Because of them, scientists now can study EZH2 and other important genes that some day will help other patients with prostate cancer."

When U-M scientists compared the prostate tissue samples, the intensity of EZH2 protein staining increased steadily as the samples progressed from benign to clinically localized prostate cancer to metastatic disease. The highest EZH2 concentrations were found in metastatic prostate cancer.

"One of the differences in our study is that we correlated EZH2 expression in prostate cells with clinical outcome," Rubin explains. "We analyzed 278 tissue samples from 64 men for EZH2 protein expression, as well as other common prognostic indicators used by pathologists, such as Gleason score, tumor stage or PSA levels. We found EZH2 protein expression to be significantly better at predicting clinical outcome than any other factor."

Another intriguing finding reported in the Nature paper was the use of a new te