Myles Brown, MD
The androgen receptor — a protein ignition switch for prostate cancer
cell growth and division — is a master of adaptability. When drug
therapy deprives the receptor of androgen hormones, thereby halting cell
proliferation, the receptor manages to find an alternate growth route. A
new study by Dana-Farber Cancer Institute and Ohio State University
scientists demonstrates how.
The shift from androgen-dependent to androgen-independent cell growth
occurs, in part, because the androgen receptor switches on an entirely
different set of genes in the latter group than in the former, the
researchers report in the July 24 issue of Cell.
In contrast to androgen-dependent prostate tumors,
androgen-independent ones experience an uptick in the activity of genes
that control cell division, or mitosis.
One such gene, called UBE2C, which causes cells to ignore a
natural pause in the division process, becomes especially active, the
researchers report. This pause, or "checkpoint," ensures that cell
division progresses normally; without it, daughter cells may grow even
more aggressively and be harder to stop.
"The evolution of prostate cancer from an androgen-dependent state to
an androgen-independent one is a key step in its progression," says
study senior author Myles Brown, MD, of Dana-Farber.
"The discovery that the androgen receptor directs a distinct gene
pathway in androgen-independent prostate cancers may lead to the
identification of genes in that pathway that can be targeted by future
Prostate cancers whose growth is fed by androgen are commonly treated
with androgen-blocking drugs. Such medications can hold the disease in
check for a period of time that varies from patient to patient, but the
tumor almost invariably gains the ability to grow without external
One of the ways such cells re-start their growth is by producing
their own androgen, scientists have discovered. Another way involves the
androgen receptor itself — the "keyhole" in the cell nucleus that
androgen molecules fit into — but the actual mechanism by which it
operates hasn't been known.
To find that mechanism, Brown's team, including co-lead authors
Qianben Wang, PhD, now of Ohio State, and Wei Li, PhD, now of Baylor
College of Medicine, charted the activity levels, or expression, of
genes controlled by the androgen receptor in androgen-dependent and
androgen-independent prostate cancer cells.
In the androgen-independent cells, they found a group of genes with
epigenetic markings — tiny attachments to DNA that switch genes on and
off — that caused them to be especially active. The genes form a
completely separate pathway from the one active in androgen-dependent
It's not known what causes those epigenetic changes to occur, but "we
are profiling the genome-wide epigenetic landscape of
androgen-dependent and -independent cancers, trying both experimental
and computational methods to identify additional regulators," says study
co-senior author X. Shirley Liu, PhD, of Dana-Farber.
"The androgen receptor clearly works by an entirely different program
in androgen-dependent and -independent cancers," says Wang. "Having
discovered that program, we'll be in a better position to understand how
it operates and how gene-targeted therapies may shut it down."
The study was supported by grants from the National Institutes of
Health, the U.S. Department of Defense, and the Prostate Cancer
Co-authors of the study include Yong Zhang, PhD, Kexin Xu, PhD,
Mathieu Lupien, Meredith Regan, ScD, Clifford Meyer, PhD, Arjun Kumn
Manrai, Michelangelo Fiorentino, MD, PhD, Christopher Fiore, Massimo
Loda, MD, and Philip Kantoff, MD, Dana-Farber; Rameen Beroukhim, MD,
PhD, Dana-Farber and the Broad Institute of Harvard and MIT; Zhong Chen,
PhD, Ohio State; Xin Yuan, MD, PhD, Hongyun Wang, PhD, and Steven Balk,
MD, PhD, Beth Israel Deaconess Medical Center, Boston; Jindan Yu, PhD,
Rohit Mehra, MD, Bo Han, and Arul Chinnaiyan, MD, PhD, University of
Michigan; Tao Wu, PhD, Harvard Medical School; Jason Carroll, PhD,
Cambridge Research Institute in the United Kingdom; Olli Janne, MD, PhD,
University of Helsinki; Mark Rubin, MD, Weill Cornell Medical College;
and Lawrence True, MD, University of Washington.