"Tamoxifen was the first drug shown capable of reducing the chances of breast cancer development in some women at risk for the disease," says Myles Brown, M.D., the study's senior author. "But many women have been reluctant to take it because of potential side effects. By understanding the basic mechanism by which the drug works, we can look for medications whose profile of effects is more advantageous to patients."

Tamoxifen is used to decrease the risk of breast cancer recurrence in women whose tumors are sensitive to estrogen. Tamoxifen acts as an anti-estrogen with these breast cells, blocking the hormone from binding to receptors and delivering growth signals.

Although tamoxifen acts as an anti-estrogen with breast cells, it shares one significant effect with estrogen: Both stimulate endometrial cells and can increase the risk for endometrial cancer. A nationwide study is underway to determine whether raloxifene, which does not stimulate the endometrium, prevents breast cancer as effectively as tamoxifen does.

Both tamoxifen and raloxifene belong to the class of agents known as selective estrogen receptor modulators, which bind inside cells at the same receptors that estrogen does. Eight years ago, the investigators proposed that the reason for the differences in activity lies in other proteins that bind to the estrogen receptor after estrogen or a selective estrogen receptor modulator has been bound to the receptor. Brown's team theorized that some of these proteins, called co-regulators, turn on genes that initiate cell division, whereas others restrain it. If more activators than repressors are attracted to the estrogen receptors, growth is stimulated; if more repressors are attracted than activators, growth is restrained.

The new study offers convincing evidence that the hypothesis is correct. Brown and Yongfeng Shang, Ph.D., the paper's lead author, found that in breast cells, both tamoxifen and raloxifene draw repressor proteins to the estrogen receptors. In endometrial cells, tamoxifen, but not raloxifene, acts like estrogen by luring activating proteins to the site, potentially stimulating the excessive growth associated with cancer.

"Our findings demonstrate that the make-up of the co-regulating proteins present in a cell determines how it will respond to treatment with different selective estrogen receptor modulators" states Brown. "This knowledge will help us better predict the range of effects of newly developed selective estrogen receptor modulators and study those that are likely to have the best spectrum of benefits."