Researchers at the Dana-Farber Cancer Institute appear to have identified the underlying mechanism that causes one of the unwanted side effects of tamoxifen. The study, published in the journal Science, may help researchers hone in on new medications that, like tamoxifen, reduce the risk of certain types of breast cancer, but do not carry tamoxifen's potentially increased risk of endometrial cancer.
"Tamoxifen was the first drug shown capable of reducing the chances of breast cancer development in some women at risk for the disease," said Dr. Myles Brown, 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 currently used to lower the risk of breast cancer recurrence in women whose breast cell growth is fueled by the hormone estrogen. In the breast, tamoxifen acts as an anti-estrogen, blocking the hormone from latching onto cells and delivering a growth signal. In some other parts of the body, however, tamoxifen and estrogen have similar effects: both substances help strengthen women's bones, for example, and may help keep their cardiovascular systems healthy.
Unfortunately, estrogen and tamoxifen also have a common detrimental effect-a heightened risk of the development of endometrial cancer. A nationwide study is under way (the STAR trial) to determine whether the drug raloxifene, which may reduce breast cancer risk without raising the risk of endometrial cancer, prevents breast cancer as effectively as tamoxifen does.
Both tamoxifen and raloxifene belong to a class of substances known as selective estrogen receptor modulators, or SERMs, which bind inside cells at the same receptors that estrogen does. In some types of cells, such as those in bones and the cardiovascular system, the effects of this binding are similar for estrogen and tamoxifen. In breast cells, however, a coupling with estrogen spurs cell growth-increasing the chances they'll become cancerous-whereas a coupling with tamoxifen or raloxifene restrains their growth. In uterine cells, estrogen and tamoxifen have the same growth-promoting effect, whereas raloxifene does not.
The challenge for scientists has been to understand and explain these differences. Knowing why tamoxifen and raloxifene behave like estrogen in some cells but not in others may help researchers "fine-tune" SERMs so they can provide the benefits of current drugs without the shortcomings.
Eight years ago, Brown and his associates proposed that the reason for the differences lay in other proteins that bind to the estrogen receptor once estrogen or a SERM is nestled there. Brown's team theorized that some of these proteins, known as co-regulators, turn on genes that initiate cell division, while others restrain it. If more activators than repressors are attracted to the estrogen receptors, growth is stimulated; if more repressors than activators are attracted, growth is restrained.
This new study appears to offer convincing evidence that the theory is right. Brown and Yongfeng Shang, PhD, 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 sparking 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 SERMs," said Brown. "This knowledge will help us better predict the range of effects of newly developed SERMs, and study those that are likely to have the best spectrum of benefits."
SOURCES:
Science, March 29, 2002; 295:5564, "Understanding Tamoxifen's Tissue-Specific Effects"
Dana-Farber Cancer Institute (http://www.dana-farber.org)
