Finding could provide targets for diagnosis, prognosis, therapy of prostate cancer

Researchers led by Dr. Shiv Srivastava from the Center for Prostate Disease Research (CPDR), Uniformed Services University of the Health Sciences (USU), report the groundbreaking discovery of the ETS-Related Gene (ERG) as one of the frequent proto-oncogene overexpressions in prostate cancer cells.

This discovery provides a very promising addition to a select group of genes, whose expression is frequently altered in prostate cancer cells and could provide novel molecular targets for diagnosis, prognosis or therapy of prostate cancer in the future.

The report by Dr. Gyorgy Petrovics et al showing ERG expression alterations in a large fraction of prostate cancer cells is published in the latest issue (May 26, 2005) of leading cancer research journal Oncogene. Using laser capture microdissected prostate epithelial cells from malignant and benign prostate tissues and GeneChips, researchers identified ERG as the first proto-oncogene that is commonly overexpressed in early-phase prostate cancer.

The cancer-causing genes known as oncogenes and tumor suppressor genes have long been known to be major factors in the development of cancer cells, and mutation or altered expression of these genes has been identified in diverse human cancers. However, for prostate cancer, which is the most common non-skin cancer and the second leading cause of cancer-related deaths among men in the U.S., the identification of oncogenes and tumor suppressor genes that are altered in most prostate cancer cells have eluded scientists thus far.

Dr. Charles Bieberich, a leading prostate cancer researcher at the University of Maryland, Baltimore Campus, who is studying the regulation and function of a prostate tissue-specific tumor suppressor, the NKX3.1 homeobox gene, stated: "I find it very exciting that overexpression of a proto-oncogene transcription factor like ERG is associated with prostate cancer at such a high frequency." Dr. Beiberich's group also studies interactions of NKX3.1 with a prostate tissue-derived ETS factor (PDEF). "These novel observations warrant further studies looking into the functional effects of ERG overexpression in model systems of prostate cancer. It is likely that additional prostate cancer-relevant gene alterations also will be discovered by the microgenomics approach used in this study."

CPDR researchers went on to assess the cancer association of ERG change in combination with other prostate cancer marker genes. They found that when they combined ERG with two other genes, DD3 and AMACR, which are described by other laboratories as commonly overexpressed in prostate cancer, the three-gene panel exhibited cancer association in 98% of the prostate cancer patients tested. This result shows promise for prostate cancer diagnosis. Intriguing correlations of ERG overexpression features also have been noted for PSA recurrence-free survival of prostate cancer patients after radical prostatectomy.

Due to the previously established oncogenic functions of ERG, CPDR researchers also propose to explore ERG as a potential therapeutic target in prostate cancer treatment.

"This is a significant new finding, but it will take time to translate this into clinically useful products. The most likely first potential clinical application could be improved detection of prostate cancer by providing a novel and functionally relevant biomarker. However, the exploration of the therapeutic potential of ERG is equally important," said Dr. Robert Vessella from the University of Washington, Seattle, who is one of the pioneers in developing new diagnostic and prognostic cellular and molecular markers for prostate cancer. Dr. Vessella is one of the primary leaders of a research effort at the University of Washington that is defining mechanisms of prostate cancer metastasis.

This discovery was the result of a highly coordinated effort by urologists, pathologists and cancer biologists from Walter Reed Army Medical Center (WRAMC), USU, the Armed Forces Institute of Pathology (AFIP), the Walter Reed Army Institute of Research (WRAIR) and the National Human Genome Research Institute (NHGRI).