Tamoxifen's Dangerous Side Is Explained

Study finds drug promotes different actions in different tissues

THURSDAY, March 28, 2002 (HealthDayNews) -- Researchers have found the molecular explanation for the dangerous side effect that keeps some women from taking tamoxifen, a drug that is known to prevent breast cancer.

In the breast, tamoxifen acts to prevent the multiplication of cells, including cancerous cells, whereas in the uterus it can act to promote the reproduction of cells, including cancerous cells, two researchers at the Dana-Farber Cancer Institute say.

That explanation already is being applied to developing medications for the prevention and treatment of breast cancer and other malignancies. A nationwide study has begun to determine whether a related drug can have the same beneficial effect as tamoxifen without its side effect.

Tamoxifen is highly effective in reducing the risk of a second breast cancer and in preventing breast cancer in high-risk women -- for example, those with close relatives who have had the disease. But it does increase the risk of cancer in the endometrium, the lining of the uterus.

The distinction is in the apparently small but critically different way that tamoxifen acts at its prime target, the receptors that enable the female hormone estrogen to act on cells, Dr. Myles Brown and Yongfeng Shang report in tomorrow's issue of the journal Science.

Tamoxifen is classified as a selective estrogen receptor modulator, or SERM. It binds to estrogen receptors and changes the way cells react to the hormone. In the breast, that means it restrains estrogen activity, reducing the growth of cells. But in the endometrium, it increases estrogen activity, encouraging cell growth.

Eight years ago Brown, who is also associate professor of medicine at Harvard Medical School, proposed that the difference was due to the other molecules that act on the receptor once tamoxifen binds to it. Now he says that theory has been proved.

Laboratory studies using cultures of cancer cells show that "in the breast, tamoxifen recruits co-activators to genes that reduce estrogen activity," Brown says. "In the endometrium, tamoxifen can recruit co-activators to genes that are responsible for the growth of endometrial cells."

Even before this final proof was in, Brown says, "almost all the major pharmaceutical companies have programs to develop new SERMs for a wide variety of indications, for breast cancer, menopausal symptoms, and osteoporosis."

And raloxifene, a SERM now marketed for treatment of osteoporosis, is being tested as a breast cancer drug. "What we don't know is how good it is in preventing breast cancer," Brown says.

However, laboratory studies have already indicated that raloxifene may have the same stimulatory effect as tamoxifen in the uterus.

Research reported last month by the Northwestern University scientist who developed tamoxifen found that raloxifene did not prevent tumor growth in laboratory mice and appeared to increase their risk of endometrial cancer.

The National Cancer Institute is continuing to sponsor a STAR trial on raloxifene to determine its effectiveness against breast cancer. The institute has begun recruiting participants at 400 medical centers, with the goal of signing up more than 13,000 menopausal women to see whether raloxifene can be as effective as tamoxifen. It will take several years to get that information.

"It's important for women at high risk of breast cancer to sign up for the STAR study," says Dawn Willis, scientific program director for the American Cancer Society. "This is the way we find out which of these drugs is better for prevention."

And a full press on SERM research is needed, she adds. "It's clear from what Dr. Brown is presenting here that there is a biological difference in breast tissue and uterine tissue," Willis says. "Other studies now have to be done on almost every kind of tissue to see what the estrogen activators are."

That includes brain tissue, she adds: "Estrogen has been shown to be helpful in cognition. There is some preliminary data suggesting that estrogen does help."

What To Do

"Women should not be overconcerned about the risk of endometrial cancer in making a decision about tamoxifen, especially women who already have had breast cancer," Brown says. "There is no doubt that it can help prevent recurrence."

For more information about the STAR trial of raloxifene, and how to inquire about enrollment, go to the National Cancer Institute.

For more about tamoxifen therapy for breast cancer, visit The National Cancer Institute.

SOURCES: Myles A. Brown, M.D., Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, Boston; Dawn Willis, Ph.D., scientific program director, American Cancer Institute, Atlanta; March 29, 2002, Science
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