A new study by scientists at Fred Hutchinson Cancer Research Center provides insight into why some men develop aggressive prostate cancer that becomes resistant to hormone-withdrawal therapy, a common form of treatment.
Researchers found that certain mutations in a protein called the androgen receptor cause advanced and invasive prostate cancer when put into otherwise healthy mice. The androgen receptor's normal function is to control growth of the prostate gland in response to cues from male hormones called androgens, which have long been thought to stimulate prostate tumors.
Because similarly defective androgen receptors have been found in prostate-cancer patients whose disease is resistant to hormone withdrawal, the finding sheds light on why most men with advanced prostate cancer treated with hormone-withdrawal therapy fail to be cured. The work opens the door to discovery of new, more effective therapies, according to Norman Greenberg, Ph.D., a member of Fred Hutchinson's Clinical Research Division.
The study is published in the Jan. 25, 2005 issue of the Proceedings of the National Academy of Sciences. The study was led by Dr. Guangzhou Han and colleagues.
Greenberg said that despite these and other earlier findings indicating a strong relationship between the androgen receptor and prostate cancer, no group had proved that it could be a key driver of disease.
"Our study is the first to demonstrate that if the androgen receptor acquires certain mutations, it can cause prostate cancer in otherwise healthy mice," he said. "Because very similar mutations have been found in androgen receptors from prostate-cancer patients whose disease is resistant to hormone-withdrawal therapy, we think this is a very significant finding."
The results suggest that prostate-cancer prevention trials involving drugs that lower a man's androgen levels should proceed cautiously, since complete androgen withdrawal seems to provide an environment that favors the development of the cancer-causing mutations. In addition, the work is the first to show that a class of proteins called steroid receptors, of which the androgen receptor is a member, can become cancer-causing genes known as oncogenes. The estrogen and progesterone receptors--two receptors that become defective in many breast cancers--are also members of this protein family.
The androgen receptor is a protein produced by prostate cells that binds to androgens, a family of chemically related hormones that includes testosterone. Although the binding of androgens to the receptor is important for healthy prostate development, the hormones may, under some conditions, stimulate the prostate-tumor cells to divide. For that reason, many men with advanced prostate cancer are treated with drugs that either block the production of androgens or the ability of the androgens to interact with their receptor.
About 90 percent of the time, prostate tumors shrink after hormone deprivation, but in most cases, it is believed that a small percentage of the tumor cells become resistant. Eventually, these resistant cells grow to become the predominant cancer, and no successful therapies have yet been developed for men with the hormone-withdrawal-resistant form of the disease.