Estrogen flips testosterone gene switch.

Talk about an odd couple. A new study suggests that estrogen, frequently considered the quintessential female hormone, can turn on genes by binding to the same protein that responds to testosterone and other androgens, the so-called male hormones.

This unexpected union only activates genes in the presence of a matchmaker protein called [ARA.sub.70], however, reports a research group led by Chawnshang Chang of the University of Rochester (N.Y). He and his colleagues describe their study in the May 12 Proceedings of the National Academy of Sciences.

The new finding hints that estrogen may play a significant role in the development of male sex organs, the investigators contend. They also speculate that estrogen's apparent ability to mimic androgens could help explain how some prostate cancer cells thrive despite treatments that eliminate androgens, which are usually necessary for prostate cells to survive.

"Our finding provides one alternative explanation for why totally blocking androgens doesn't completely block androgen receptor activity," says study coauthor Shuyuan Yeh.

While scientists reject a simplistic categorization of estrogen and testosterone as female and male hormones--both sexes make various forms of estrogens and androgens--the hormones were thought to regulate largely distinct groups of genes. Estrogens latch onto so-called estrogen receptors, which in turn bind to and activate select genes. Similarly, testosterone and related hormones bind to androgen receptors, which turn on a different array of genes.

Chang's group, which years ago discovered the androgen receptor, more recently found that the presence of [ARA.sub.70] magnifies the receptor's response to androgens. The researchers then decided to reexamine whether estrogens can turn on genes controlled by the androgen receptor. Past studies had indicated that estrogen could do so only when present in much higher concentrations than those found naturally in the body or when the androgen receptor has a mutation that makes it responsive to estrogen.

Working with cells genetically engineered to make [ARA.sub.70] and the androgen receptor, the investigators found that, in the presence of [ARA.sub.70], one form of estrogen activates some of the genes normally turned on by the receptor in response to androgen.

Further test-tube experiments identified a mutation in the androgen receptor that blocks estrogen's ability to turn on those genes--without affecting an androgen's ability to do so. The team also discovered that a man with abnormally developed reproductive organs had the same mutation. His androgen receptor's inability to respond to estrogen may help explain those developmental problems, the investigators suggest.

Several androgen researchers contacted by Science News questioned whether the new findings truly establish that estrogen interacts with the androgen receptor in the body.

"This won't be enough to get people to accept that estrogen acts through the androgen receptor, but it raises the possibility. It's provocative," says Steven P. Balk of Beth Israel Hospital in Boston, who studies the role of androgens and their receptor in prostate cancer. "It won't be trivial to prove that this particular pathway is important."

The researchers are in the process of creating mice with a defective [ARA.sub.70] gene, animals they hope will help further elucidate estrogen's relation to the androgen receptor. If estrogen does activate genes controlled by the androgen receptor, drugs that interfere with the function of [ARA.sub.70] may block this process and thus prove a useful addition to treatments for prostate cancer, notes Yeh.