Prostate-cancer driver revealed

A new study from the Clinical Research Division provides insight into why some men develop aggressive prostate cancer that becomes resistant to hormone-withdrawal therapy, a common form of treatment.

The study, led by Dr. Guangzhou Han and colleagues in Dr. Norman Greenberg's lab, 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.

The study is published in the online early edition of the Proceedings of the National Academy of Sciences.

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 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.

Mutatant receptors

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.

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, although their potential role as oncogenes has not yet conclusively been demonstrated.

To determine the role of the androgen receptor, Han, a postdoc in Greenberg's lab, first conducted an analysis of mice that had been genetically engineered to develop prostate cancer. After cancer developed, the mice were castrated to remove the primary source of circulating androgen — a situation similar to that in men who are deprived of androgen with medications. Han then examined mutations in the androgen receptor that arose in mice whose disease became resistant to hormone deprivation.

Role of co-regulators

He identified several mutations that impair the ability of the receptor to interact with proteins called co-regulators. Co-regulators help the receptor to carry out its functions at the proper time; therefore, lack of interaction between the receptor and the appropriate co-regulators is thought to spur cancer development. Analogous mutant receptors also have been found in human prostate cancers.

Han then asked what would happen if he put the mutant receptors into otherwise healthy mice that also contained a normal version of the androgen receptor. He found that 100 percent of the time, the addition of one particular mutant receptor cause rapid development of a precancerous condition that progressed to advanced disease. In contrast, mice with an extra copy of a normal receptor, as well as mice with one normal receptor and an unrelated type of mutant receptor, did not cause cancer.

"This demonstrates a causal role for certain androgen-receptor mutations in prostate cancer," Greenberg said.

New drug targets

Not all men with hormone-withdrawal-resistant disease develop such mutations, Greenberg said. Yet hormone-deprivation treatment can create a situation in some prostate tumors in which such mutations give a growth advantage to cancer cells.

Such mutant receptors might prove to be good drug targets, Greenberg said.

"These and other mutant forms of the receptor should be potential targets for new drugs that will be particularly effective in men whose cancers have these mutations and related events," he said. Because androgen deprivation has numerous side effects — including bone loss and sexual dysfunction — drugs that specifically attack the cancer-causing protein would be much more desirable than existing therapies.

Drugs that effectively work against certain mutant proteins have been developed for other cancers, including Iressa for lung cancer and Gleevec for chronic myeloid leukemia.

Since the mutations Greenberg's lab studied appear to affect one specific function of the androgen receptor, it may also be possible to develop drugs that target other proteins that collaborate with the androgen receptor in this pathway. Greenberg's lab is now studying this pathway, with the hope of providing insight into drug discovery.