A group of scientists has proposed an explanation of why tamoxifen loses effectiveness. Donald P. McDonnell, PhD, associate professor in the department of pharmacology and cancer biology at the Duke University Medical Center, and colleagues suggest tamoxifen initially works by preventing estrogen from binding to a receptor within breast cells. Tamoxifen changes the shape of the receptors, inactivating them, and in doing so prevents these receptors from participating in processes required for cancer cell growth.

The researchers' findings, which were published in a recent issue of the journal Science, indicate the cells eventually adapt and learn to recognize tamoxifen as an "estrogen," and cell growth may proceed.

Tamoxifen is used to treat early-stage and recurrent breast cancer and is also being studied as a means of preventing cancer in healthy women. However, in advanced breast cancer, tamoxifen resistance usually develops within two to five years, and some studies suggest there may be little or no benefit to taking the drug for more than five years, Dr. McDonnell said. "Tamoxifen is a very good drug, and a very complicated drug. When it's not effective, we want to understand why," he said.

The researchers believe their theory about tamoxifen resistance is a step toward extending the benefits of the drug and could help in developing new drugs that could combat breast cancer while also protecting women from conditions such as osteoporosis and heart disease.

During several years of research into tamoxifen, Dr. McDonnell and his colleagues discovered a method of manipulating the estrogen receptor that may restore the drug's anti-estrogen effects.

Discoveries about tamoxifen resistance do not yet answer questions such as how long women should take tamoxifen or what other drugs could be used to treat or prevent cancer if tamoxifen is no longer effective, he said. A number of drugs are being tested that can block the negative effects of estrogen in breast cells while not disrupting its beneficial effects in the prevention of osteoporosis and heart disease.

However, tamoxifen is now the best drug for preventing the spread of breast cancer and the occurrence of new breast cancers in women who have had an estrogen receptor-positive breast tumor, said Debbie Saslow, PhD, director of breast and cervical cancer for the American Cancer Society (ACS).  "There is a lot of research going on to find even better drugs, and the results of this study will be useful in that process," she said.

"We have known about tamoxifen resistance for a long time," Dr. Saslow added. "That is why tamoxifen is prescribed for no more than five years, because clinical studies had shown that after five years the benefit is lost and it actually is harmful."