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Estrogen may play key role in prostate cancer, WCMC researchers find

Using a breakthrough technology that reveals new data from 30-year-old samples, researchers led by Weill Cornell Medical College (WCMC) pathologist Mark Rubin have pinpointed the hormone estrogen as a key player in about half of all prostate cancers.

Estrogen-linked signaling helps drive a unique and aggressive form of the disease caused by a chromosomal translocation, the researchers found, which, in turn, results in the fusion of two genes.

"Fifty percent of prostate cancers harbor a common recurrent gene fusion, and we believe that this confers a more aggressive nature to these tumors," said Rubin, professor of pathology and laboratory medicine and vice chair for experimental pathology at WCMC. Rubin is also attending pathologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"Interfering with this gene fusion -- or its downstream molecular pathways -- will be crucial in the search for drugs that fight the disease. Based on our new data, we now believe that inhibiting estrogen may be one way of doing so," Rubin said.

The findings are published in the May 27 online edition of the Journal of the National Cancer Institute. Rubin conducted the study while at the Brigham and Women's Hospital, in collaboration with researchers at the Massachusetts Institute of Technology's Broad Institute and Harvard University.

Experts have long understood that male hormones help spur prostate cancer, and androgen-deprivation therapy is a first-line treatment against the disease. But the disease can progress despite androgen reduction, suggesting that other pathways might be at work.

"So, we wanted to learn more -- what is the genetic and molecular 'fingerprint' of this aggressive subset of prostate tumor?" Rubin asked.

Answering that question required the analysis of 455 prostate cancer samples from trials in Sweden and the United States that were conducted as far back as the mid-1970s. But because the samples were placed in fixative, which causes RNA to fragment, the researchers first needed to develop new methods for retrieving the genetic information.

They came up with a technique to target small fragments of RNA, enabling them to amass information on more than 6,000 genes and discover an 87-gene "signature" that distinguishes fusion-positive cancers from other prostate malignancies.

A close analysis of the signature yielded a surprise: that estrogen-dependent molecular pathways appear to play a crucial role in regulating (and encouraging) this aggressive subset of prostate cancer.

While estrogen is typically thought of as a female hormone, men produce it as well. The finding could have implications for prostate cancer research, including drug development.

"The technological achievement of using fixed samples that were up to 30 years old is significant," said Rubin. "In the future, we hope to explore banked tissues from clinical trials to help understand why they failed. This should lead to insight for designing the next trial."

The work was funded by the U.S. National Institutes of Health, a Prostate SPORE grant at the Dana-Farber/Harvard Cancer Center, Swiss Foundation for Medical-Biological Grants SSMBS, U.S. Department of Defense and the Prostate Cancer Foundation.

Ernie Mundell is a freelance writer for Weill Cornell Medical College.

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