Apr. 18, 2002 Hopkins cancer researchers have identified a new genetic culprit-with dietary links-in the initiation of prostate cancer. Their findings are reported in the April 15, 2002, issue of Cancer Research.
Cells taken from prostate cancers show a nine-fold increase in expression by a gene called AMACR (x-methylacyl-CoA racemase), a team of Hopkins investigators report. "This gene appears to play an important role in breakdown of branched chain fatty acid molecules such as those found in dairy products and beef," says William B. Isaacs, Ph.D., professor of urology and oncology at the Brady Urological Institute and Kimmel Cancer Center* at Johns Hopkins, and senior author of this study.
The Hopkins scientists caution that the link, if any, between increased expression of AMACR and eating beef and dairy foods is unclear and is the focus of ongoing research. The fatty acid molecules metabolized by an enzyme made by the AMACR gene are low in chicken and most fish. Several studies have shown diets high in red meat to be associated with an increased risk of prostate cancer.
"What we've learned about AMACR could not only serve as an excellent early marker for prostate cancer but also could identify new dietary or chemical means of preventing the disease," says Angelo M. De Marzo, M.D., Ph.D., co-author of the study and assistant professor of pathology, oncology, and urology at Johns Hopkins.
In the current study, Hopkins researchers used a comprehensive "gene chip" approach to simultaneously analyze the expression of more than 6500 genes and found that the AMACR gene was overexpressed in prostate cancers. They confirmed this by examining 168 prostate cancer tumors using a tissue microarray that rapidly evaluates gene expression. Using automated computer technology, researchers displayed the tissue microarrays to speed up the identification of relationships among genes and changes in normal and cancer cells.
More than 95 percent of the tumors analyzed showed overexpression of the AMACR gene, making it one of the most consistent biological markers known for prostate cancer. Similar overexpression patterns were found in precancerous lesions, called high grade prostatic intraepithelial neoplasia.
"Since AMACR enzymatic activity is not found in most normal tissues, it could be an excellent candidate for the development of molecular probes for non-invasive detection of prostate cancer and as a potential drug target," says June Luo, Ph.D., postdoctoral fellow at Johns Hopkins and lead author of the study.
The AMACR gene was first revealed in the last two years as a potential prostate cancer marker by researchers at the Corixa Corporation and then at the University of Massachusetts Medical School in Worcester. Since then, it has been independently identified by the Hopkins group and a research team at the University of Michigan.
The search for better prostate cancer diagnostic tools is driven in part by uncertain outcomes of needle biopsies. "As many as 15 percent of needle biopsies are inconclusive and must be repeated," says De Marzo. A prostate needle biopsy is an uncomfortable procedure that requires repeated needles to be placed through the rectum into the prostate to retrieve prostate cells for examination under the microscope. "Markers that can enhance diagnostic accuracy the first time are urgently needed," he adds.
The Hopkins group currently is studying the effectiveness of using AMACR in combination with a more commonly prostate cancer-associated gene, p63, to evaluate prostate needle biopsies.
This research was funded by the Peter J. Sharpe Foundation, the Charlotte Geyer Foundation and the National Cancer Institute.
In addition to Drs. De Marzo Isaacs and Luo, other Hopkins participants in this research include Shan Zha, Welsey R. Gage, Thomas A. Dunn, Jessica L. Hicks, Christina J. Bennett, Charles M. Ewing, and Elizabeth A. Platz. This work was done in collaboration with Sacha Ferdinandusse and Ronald J. Wanders, Ph.D., from the University of Amsterdam, The Netherlands, and Jeffrey M. Trent, Ph.D., from the National Human Genome Research Institute.
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