Molecular Mechanisms in Prostate Cancer Linked to Ewing's Sarcoma

Medical researchers at Indiana University Bloomington are reporting that prostate cancer may be much more closely related to Ewing’s sarcoma than previously recognized. They are reporting that they have found evidence that links prostate cancer with a rare form of cancer that affects children and young adults. 

Writing in the journal Cell Reports, they report that the molecular mechanism that triggers the rare disease Ewing's sarcoma could act as a potential new direction for the treatment of more than half of patients with prostate cancer.

"This research shows that the molecular mechanism involved in the development of most prostate cancers is very similar to the molecular mechanism known to cause Ewing's sarcoma," said Peter Hollenhorst, PhD, an associate professor in the Medical Sciences Program at IU Bloomington, a part of the IU School of Medicine, Bloomington, Indiana. "It also suggests that this mechanism might be used to explore a common treatment for both diseases."

Among 28 ETS (erythroblast transformation-specific) genes, four are known to produce proteins that cause prostate cancer (ETV [ETS variant gene]1, ETV4, ETV5 and ERG). ERG (estrogen-regulated gene) is implicated in more than 50% of all prostate cancers. The other three combined (ETV1, ETV4, and ETV5) play a role in about 7% of prostate cancers.

Ewing's sarcoma results from errors in the chromosome repair process that causes the merger of two separate gene segments into a mutant hybrid gene. One of these genes is EWS (Ewing’s sarcoma gene) and the other is a gene that produces ETS proteins. This current study is the first to show that the proteins produced by the EWS gene interact with all four ETS proteins known to trigger prostate cancer. In addition, the researchers found the EWS protein only interacts with proteins from these four harmful ETS genes--not the other 24 ETS genes.

Hollenhorst said these study findings suggest that any compound that disrupts EWS-ETS interaction may specifically inhibit the function of the four oncogenes. The ETS genes implicated in prostate cancer interact with the unmutated form of the EWS gene.

The majority of the experiments involved both laboratory and mouse models in order to observe the behavior of ETS oncogenes in prostate cancer cell cultures to reveal interaction with EWS proteins. In addition, the investigators introduced the ERG gene into normal human prostate cells in mice, which triggered the formation of tumors. The scientists then introduced an artificial mutation in the ERG gene to disrupt interaction with the proteins produced by the EWS gene. In these mice, the tumors failed to form.

Hollenhorst said the findings suggest the interaction between ERG and EWS is important for tumor formation and EWS interacts specifically with ETS proteins, which promote prostate cancer. In conclusion, researchers demonstrated that EWS is required for oncogenic ETS functions in prostate cells.   Hollenhorst and colleagues are now searching for molecules that could potentially disrupt ETS-EWS interaction.