Receptor May Explain Male
Dominance in Liver Cancer
liver cancer without androgen receptor;
Right: liver cancer with androgen
University of Rochester Medical Center).
19, 2010 -- A University of Rochester study helps
to explain why men get liver cancer more often than
women and opens the door for a new treatment pathway,
by showing a direct link between the androgen receptor,
which is more active in men, and the hepatitis B virus
as it relates to the deadly cancer.
The study is published May 19, 2010, in Science
Translational Medicine, a new journal from the
American Association for the Advancement of Science,
Primary liver cancer is the fifth most common cancer
in men. It often arises after infection from the hepatitis
B virus (HBV), which is widespread across the globe
and growing in the United States. Other studies of
liver cancer have focused on risk factors such as
age, family history, and use of alcohol and cigarettes,
but those epidemiology studies have not explained
the mechanisms driving hepatocellular carcinoma and
why men are more susceptible.
Now, corresponding author Chawnshang Chang, PhD, the
George Hoyt Whipple Distinguished Professor of Pathology
at the University of Rochester Medical Center, and
colleagues, showed that the androgen receptor (AR),
a protein that mediates male sex hormones, promotes
liver cancer when hepatitis B is present by altering
DNA replication of the virus. Chang's laboratory created
a mouse model for HBV-induced liver cancer and reported
that knocking out AR suppressed the HBV-induced cancer.
According to an accompanying editorial in the journal,
the identification of the AR pathway is a potential
new treatment target that could translate to the clinic.
"Our study is the first in vivo evidence to demonstrate
a direct connection between HBV-induced liver cancer
and the AR," Chang said. "This is important
because so far most work has focused on eliminating
total serum androgen levels, a type of therapy that
has shown little success."
"This important paper offers insight into something
we have long observed but not entirely understood,
namely that men with HBV are much more likely to develop
cancer than women with the same infection," added
Aram Hezel, MD, a gastrointestinal oncologist at the
James P. Wilmot Cancer Center at University of Rochester
Medical Center. "This is great use of the tools
of genetics and mouse modeling to explain a clinical
finding, and most importantly turn our attention to
potentially more promising treatment approaches for
patients with hepatocellular carcinoma."
"This study also raises the possibility of prevention
among men with HBV infection through inhibition of
the androgen receptor," Hezel said. "The
potential impact on clinical care is great."
For decades Chang has focused on the particular role
of the AR in human health. In 1988 he successfully
cloned AR, which led to breakthroughs in several AR-related
diseases such as prostate and bladder cancer, and
Kennedy's neuron disease, a rare and progressive motor
disorder similar to Lou Gehrig's disease, and that
affects only men.
The AR is central to the action of testosterone and
has a profound effect on many organs. In previous
experiments, Chang has shown that mice without AR
have dramatically lower rates of bladder cancer, a
cancer that strikes men three times more often than
Male dominance in liver cancer suggested that the
AR would be a key factor, as well. (About 74 percent
of liver cancer cases occur in men.) Chang's objective
was to locate a new pathway for treatment that would
not require depletion of androgen levels in the entire
body, which amounts to castration and causes severe
side effects for patients.
His study took the first step toward demonstrating
this could be done, at least for early stage liver
cancer. Researchers showed that an experimental drug,
ASC-J9, attacked and degraded the faulty AR, and suppressed
liver tumors in mice.
Chang developed ASC-J9 earlier this decade and first
reported on its clinical potential in March 2007 in
the journal Nature Medicine. The drug is a
synthetic compound loosely based on the compounds
found in curcumin, the polyphenol that gives the spice
tumeric its yellow color. It has been used for centuries
as a folk medicine in Asia and India. In this case,
however, scientists significantly altered the natural
substance to be more powerful, and are carefully screening
it for safety and effectiveness.
AndroScience Corp., a biotech company founded by Chang
and others in 2000, is evaluating ASC-J9 in several
clinical settings, although not yet in the treatment
of liver cancer, Chang said. The URMC owns a stake
in AndroScience and has licensed several of Chang's
In the current study, researchers found that AR cooperates
with the hepatitis B virus to trigger the expression
of several oncogenes, resulting in normal liver cells
transforming into cancer cells. Furthermore, they
showed that liver tumors without the AR had fewer
proliferating cancer cells, which helps to explain
the gender disparity in the disease.
Some of the findings are in agreement with earlier
studies by Chang's lab on the role of AR in prostate
cancer. Just as in prostate cancer, the liver tumor
microenvironment is rich in various cell types, each
of which has a distinct role in promoting the cancer.
"It will be interesting to see if targeting AR
at different stages or in different liver cancer cell
types may also lead to differential effects during
the progression of cancer," the paper concluded.
The hepatitis B and C viruses account for approximately
80 percent of primary liver cancer cases worldwide.
Newborn vaccines and screenings for HBV and HCV, particularly
in Asian and African countries, have reduced the incidence
of liver cancer in later years. Still, an estimated
560,000 new cases are diagnosed annually. In high-risk
areas such as China, Japan and sub-Saharan Africa
the male-to-female ratio of liver cancer can be as
high as 8 to 1. The current best treatment is surgery;
median survival is generally six months.
Investigator affiliations: Institute of Basic Medical
Sciences, National Cheng Kung University, Tainan,
Taiwan; George Whipple Lab for Cancer Research, Departments
of Pathology and Urology and Wilmot Cancer Center,
University of Rochester Medical Center, Rochester,
NY; Sex Hormone Research Center, Graduate Institute
of Clinical Medical Science, Department of Obstetrics
and Gynecology, China Medical University/Hospital,
Taichung, Taiwan; Division of Hematology-Oncology,
Department of Internal Medicine, Chang Gung University/Memorial
Hospital, Taoyuan, Taiwan; Department of Molecular
Microbiology and Immunology, University of Southern
California, Los Angeles, CA.