Link Between Molecular Mechanisms in Prostate Cancer and Ewing Sarcoma Found

Key Points

  • Proteins produced by the EWS gene (whose fusion with another gene results in Ewing’s sarcoma) interact with all four ETS proteins known to trigger prostate cancer.
  • The EWS protein only interacts with proteins from these 4 harmful ETS genes, not the other 24 ETS genes not found to play a role in prostate cancer (there are 28 ETS genes in total).
  • Results indicated that the interaction between ERG and EWS is important for tumor formation in prostate cancer. 

Medical researchers at Indiana University (IU) Bloomington have found evidence for a link between prostate cancer, which affects millions of men aged 50 and older, and Ewing's sarcoma, a rare form of cancer that affects children and young adults.

The results of the study, reported by Kedage et al in Cell Reports, suggest that the molecular mechanism that triggers Ewing's sarcoma could act as a potential new direction for the treatment of more than half of all patients with prostate cancer.

A form of bone and soft-tissue cancer that affects about 1 in 1 million children and young adults aged 10 to 19 years, Ewing's sarcoma is terminal in 44% of teens aged 15 to 19 and 30% of children. Over 100,000 men are diagnosed with prostate cancer each year in the United States, with more than 99% of cases occurring after age 50.

“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, Associate Professor in the Medical Sciences Program at IU Bloomington, a part of the IU School of Medicine, and member of the Indiana University Melvin and Bren Simon Cancer Center. “It also suggests that this mechanism might be used to explore a common treatment for both diseases, one of which is not often pursued by drug companies due to its rarity.”

Genetic Findings

There are 28 genes in the human body known as ETS genes, four of which are known to produce proteins that cause prostate cancer. These 4 oncogenes are called ETV1, ETV4, ETV5, and ERG, the last of which has been implicated in over 50% of all prostate cancers. The other 3 combined 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 fusion genes is called EWS; the other is a gene that produces ETS proteins.

Dr. Hollenhorst's 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. Moreover, the EWS protein only interacts with proteins from these 4 harmful ETS genes, not the other 24 ETS genes not found to play a role in prostate cancer.

“A molecular mechanism that sets these four genes apart from the ones that don't trigger cancer has never been identified—until now,” Dr. Hollenhorst said. “This is significant because it suggests that any compound that disrupts EWS-ETS interaction would specifically inhibit the function of the four oncogenes and not the others, which play important roles in the healthy function of the body.”

The team also found the ETS genes implicated in prostate cancer interact with the unmutated form of the EWS gene. In Ewing's sarcoma, the small blue tumors that characterize the disease do not occur unless mutation occurs.

Study Methodology

IU scientists used a combination of laboratory experiments and mouse models to observe the interaction of EWS and ETS proteins in prostate cells. The majority of the experiments involved observing the behavior of ETS oncogenes in prostate cancer cell cultures to reveal interaction with EWS proteins.

In experiments at the IU School of Medicine, they also 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.

“Together, the results indicated that the interaction between ERG and EWS is important for tumor formation,” Dr. Hollenhorst said. “We chose to focus our greatest efforts on the ERG protein since it is responsible for over 50% of all prostate cancers, and therefore has the potential to benefit the greatest number of people.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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