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Derivative provides clues to better Breast
Newswise — Retinoic acid, a derivative of
vitamin A, could lead researchers to a new
set of drug targets for treating breast
cancer, researchers from the University of
Chicago report in the June 25, 2009, issue
of the journal Cell.
The most common forms of breast cancer are
fueled by the female hormone estrogen. By
comparing the effects of estrogen and
retinoic acid on the entire genome, the
researchers found that they have a
They alter the expression of many of the
same genes, with estrogen tipping the scales
towards cell proliferation and retinoic acid
restoring the balance by inhibiting cellular
This balanced control of gene expression
regulates fundamental cellular processes,
say the authors. When it is dysregulated, it
can lead to cancer.
"Understanding all the components of this
process could be used against breast cancer
care in three ways," said study leader,
Kevin White, PhD, professor of human
genetics and director of the Institute for
Genomics and System Biology at the
University of Chicago.
suggests new ways to think about preventing
the disease in those at high risk. It offers
molecular tools that could provide a more
precise diagnosis and predict outcomes.
could also be used to enhance current
therapies, making existing drugs, such as
tamoxifen, that selectively block estrogen's
effects even more powerful, or even to
develop new anti-cancer drugs."
White's team studies the effects of nuclear
receptors, a class of proteins found within
cells that control the response to various
When a hormone enters a cell and connects
with its receptor, that receptor alters the
pattern of expression of specific
genes--often hundreds or more.
For this study, White and colleagues Sujun
Hua and Ralf Kittler focused on the retinoic
Retinoic acid, known for its anticancer
effects and already in use to treat a rare
form of leukemia, has also been associated
with anti-proliferative changes in breast
So the team combined two laboratory
techniques--a process known as "ChIP-chip
analysis" that blends chromatin
immunoprecipitation (ChIP), to see where the
retinoic acid receptors bound to the genome,
with micro-array gene-chip analysis, to
measure expression levels of specific genes.
The combination enabled them to map out all
the genetic effects of retinoic acid and its
receptors in a cell line derived from
patients with breast cancers that were
fueled by estrogen.
They found that 39 percent of the genomic
regions bound by estrogen receptor alpha
overlapped with those bound by retinoic
also found that the binding of estrogen and
retinoic acids receptors to target sites
were often mutually exclusive.
This means the two hormones compete to
activate or repress many of the same genes.
The two signaling pathways were mainly
Estrogen increased expression of 139 genes
that retinoic repressed. Retinoic acid
activated 185 genes that estrogen repressed.
For about 140 genes, estrogen and retinoic
acid had the same effect.
"Collectively, note the authors, "these
findings indicate an extensive crosstalk"
between the effects of estrogen and retinoic
acid. Despite their opposing effects,
certain versions of the estrogen and
retinoic acid receptors actually activate
This provides "an additional level of
control," say the authors, "for achieving a
balanced regulation of gene expression."
This competition between the two signals
also provides a new tool to predict
outcomes. The researchers compared the
effects of retinoic acid on tissues from 295
breast cancer patients against the results
from their initial study using a typical
breast cancer cell line.
found that the more responsive a tumor was
to retinoic acid, the better the odds of
long-term relapse-free survival.
Some of the genes that respond to retinoic
acid were expressed even in
difficult-to-treat tumors, such as those
that do not have estrogen receptors or the
molecule targeted by the drug Herceptin, the
so-called double- or triple-negative breast
"Some of these genes may provide new drug
targets," White said.
Although retinoic acid is approved for
treatment of leukemia, it can be quite toxic
and patients can develop resistance to the
This study suggests a long series of
downstream targets that are activated by the
"The goal would be to develop drugs that
could activate these cancer-inhibiting
targets," said White. “Retinoic acid itself
is probably not the solution because of its
side effects and metabolic byproducts,"
cautioned, "but our results provide a
molecular justification for finding ways to
overcome its limitations in the clinic.”
"This work reveals important insights on the
interplay between vitamin A and estrogen
action," said Myles Brown, MD, professor of
medicine at Harvard Medical School and the
Dana Farber Cancer Institute.
"These insights will hopefully lead to new
approaches for the prevention and treatment
of the most common form of breast cancer."
The National Institutes of Health and a
grant from the Chicago Biomedical Consortium
(CBC) with support from the Searle Funds at
the Chicago Community Trust funded the