Scientists find one reason why bladder cancer
hits more men
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.
Nearly a decade ago, Chang showed that molecules other than
male hormones like testosterone are able to
activate the androgen receptor. That finding
isn't simply gathering dust in textbooks; it
likely explains why hormone therapy for men in
the advanced stages of prostate cancer
ultimately fails. His work explained a
long-baffling phenomenon in these patients,
where drugs that work well for a few years
suddenly make the cancer grow again late in the
course of the disease.
In the recent paper, Chang continued this line of work, only
in bladder cancer instead of prostate cancer. He
took a closer look at the nearly disease-free
male mice that didn't get bladder cancer despite
exposure to a carcinogen. Some of those mice
then received a drug known as DHT, a male
hormone. In theory, such a drug only works if
the androgen receptor is present, so the drug
should not have had an effect. But 25 percent of
these mice then got bladder cancer, clear
evidence that the hormone is able to somehow
side-step the traditional, receptor-mediated,
pathway and still have an effect.
The work shows starkly that simply cutting off the supply of
hormones like testosterone will have only a
limited effect. The androgen receptor can still
play a crucial role in the development of
cancer, even without the hormones. The team has
shown in other studies that even female hormones
such as estrogen can turn on the androgen
receptor.
"The activity of the androgen receptor is different from the
activity of hormones that target the receptor,"
said Chang. "We've shown very clearly that even
without these hormones, the receptor is still
active in the development of cancer. This is
crucial information as doctors seek to develop
treatments for diseases like prostate or bladder
cancer in men."
To knock out the androgen receptor, the team used a compound
known as ASC-J9, a synthetic chemical compound
that is loosely based on a compound found in
curcumin. Chang's laboratory, in collaboration
with San Diego-based AndroScience Corp., has
screened hundreds of compounds for their
activity involving the androgen receptor. Just
last month, the team showed that ASC-J9 offers
promise against a rare neuromuscular disease
known as Kennedy's disease.
The compound is now being tested as a cream to treat acne in
a clinical trial run by AndroScience, a biotech
company founded by Chang, Charles C-Y Shih, and
Por-Hsiung Lai in 2000. The University owns a
stake in the company, which has licensed several
of Chang's research findings.
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The first author of the paper is Hiroshi Miyamoto, M.D.,
Ph.D., who was a post-doctoral researcher in
Chang's laboratory and is now a medical resident
in the Department of Pathology and Laboratory
Medicine. Miyamoto was joined by several of his
former colleagues at Yokohama City University
Graduate School of Medicine in Yokohama, Japan,
who did much of the work with the human bladder
cancer cell lines and analyzed levels of the
androgen receptors. Collaborators there include
Hitoshi Ishiguro, Hiroji Uemura, Yoshinobu
Kubota, and Yoji Nagashima.
Other authors of the paper, in addition to Chang and Messing,
are Zhiming Yang, a former graduate student now
at Zhejang University and 2nd Hospital in
Hangzhou, China; Yei-Tsung Chen and Yueh-Chiang
Hu, former graduate students and now researchers
at Harvard; Yu-Jia Chang, formerly a
post-doctoral researcher with Chang, now an
assistant professor at Taipei Medical University
and Hospital in Taipei, Taiwan; former graduate
student Meng-Yin Tsai, now at Chang Gung
Memorial Hospital in Kaohsiung, Taiwan; and
Shuyuan Yeh, associate professor of Urology.
