Scientists have discovered one of the reasons why bladder cancer is so much more prevalent in men than women: A molecular receptor or protein that is much more active in men than women plays a role in the development of the disease.
The finding could open the door to new types of treatment with the disease.
In an article in the April 4 issue of the Journal of the National Cancer Institute, Chawnshang Chang, Ph.D., of the University of Rochester Medical Center and colleagues show that the androgen receptor, which is central to the action of testosterone and other hormones that are much more plentiful in men than women, appears to play a key role in the disease.
In experiments reported in the journal, mice without the receptor had dramatically lower rates of bladder cancer compared to normal mice with the receptor, and human cancer cells with the receptor were much more aggressive than those without it. Mice develop bladder cancer for many of the same reasons people do, and the molecular signals that control cancer development in mice mirror those in humans.
The disease hits about three times as many men as women, including estimates of 50,000 men and 17,000 women in the United States in 2007, according to the American Cancer Society. Some scientists have suspected that male hormones working in concert with the androgen receptor might play a role, but hard evidence has been minimal until now, said Edward Messing, M.D., a bladder cancer expert and chair of Urology. Instead, scientists have suspected that factors like greater exposure of men to cigarettes and industrial chemicals has been responsible.
"For many years, people have recognized that men are more likely than women to get bladder cancer," said Messing, one of the authors of the paper. "More and more women are smoking and working with chemicals in the workplace, yet their bladder cancer rates have not really changed much. There is no longer any question that the androgen receptor is playing a role in bladder cancer."
The work by a team of collaborators from Rochester and from Yokohama City University Graduate School of Medicine in Japan was led by Chang, director of the George Whipple Laboratory for Cancer Research at the University of Rochester Medical Center and a faculty member in the departments of Urology and Pathology and the James P. Wilmot Cancer Center.
Chang is an expert on the androgen receptor, which is central to many diseases and conditions, most notably prostate cancer. For that disease, hormone therapy to block the supply of hormones that turn on the receptor is a staple of treatment for men with advanced disease. The new findings open the possibility that perhaps someday, drugs that target male hormones, like those used against prostate cancer, might help men with bladder cancer.
The strongest evidence for the involvement of male hormones in bladder cancer was what happened when Chang's team disabled the androgen receptor in mice. While their normal counterparts with the androgen receptor got significant levels of bladder cancer when exposed to a carcinogen , 92 percent of the males and 42 percent of the females , not a single mouse whose androgen receptor was knocked out developed bladder cancer. The mice without the receptor also had significantly fewer premalignant changes in their bladder.
Besides opening the door to possible new treatments, Chang says the findings could help doctors decide which cases of bladder cancer are most likely to re-occur. His team found a correlation between the frequency of the androgen receptor in tumor cells and the recurrence of the tumor , tumors more likely to re-appear had more of the protein. If the finding holds up in wider testing in human tumors, it would help doctors know which patients to treat aggressively right from the start.
The JNCI paper is the latest installment in a body of research Chang has compiled that shows that the story of the androgen receptor and male hormones like testosterone is much more complex than was once thought. For years it's been widely thought by doctors and scientists that all male hormones, and only male hormones, work through the androgen receptor.
But he felt there was more to the story. If anyone would know, it would be Chang, who in 1988 was the first person to clone the androgen receptor, and was the first to discover that the protein needs molecular allies called co-factors to accomplish many of its tasks. Now more than 80 co-factors are known, offering many new targets to stop conditions like male-pattern baldness and diseases like prostate cancer.