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C o l u m b i a U n i v e r s i t y RECORD
June 10, 2003
Columbia Researchers Find Hormone Estrogen Can be a Cancer-Causing Agent
BY SUSAN CONOVA
I
t's disconcerting to think
that a natural hormone
circulating in significant
amounts through the bodies of
half the world's population is a
carcinogen, but it's now official. In December, the National Institute of Environmental
Health Sciences (NIEHS)
added estrogen to its list of
known cancer-causing agents.
For years, estrogen has been
a suspected carcinogen, since
strong epidemiological evidence associates the hormone
to breast, endometrial, and
uterine cancers. Women who
begin menstruating early, or
who start menopause late, produce more estrogen over their
lifetimes and have a higher
risk of breast cancer. Recently,
the clinical trial of estrogen
plus progestin treatment therapy was terminated because of
an increased risk of breast cancer.
Despite estrogen's new status on the NIEHS listing, not
all forms of the hormone are
carcinogenic. And that has
called into question the route
cancer-causing estrogens take
in stimulating tumors.
A new study by Mailman
School of Public Health
researchers shows that more
than one sequence of steps is
necessary before estrogen can
cause cancer. In addition to a
hormone
receptor-mediated
process, a second process is also
required, says the study's lead
author, Hari Bhat, assistant professor of environmental health
sciences. Their results suggest
that blocking the second pathway could prevent estrogeninduced cancers. But they also
suggest that even non-carcinogenic estrogens can cause
cancer given the right conditions. This research was published in the April 1 Proceedings of the National Academy of
Sciences.
Estrogen was originally
believed to cause cancer by
helping cells proliferate. After
the hormone binds to its receptors in a cell, it turns on hormone-responsive genes that
promote DNA synthesis and
cell proliferation. If a cell happens to have cancer-causing
mutations, those cells will also
proliferate and have a chance
to grow into tumors.
"But if cell proliferation via
receptor-mediated processes is
the only mechanism, then all
estrogens should cause cancer," Bhat says. "So it is
hypothesized that estrogen
metabolism may play a key
role in estrogen-induced cancers because different estrogens differ in how they're broken down in the cell."
The picture above shows renal tumors, labeled “T”, and congested
tubules, noted by arrows, of male Syrian hamsters induced by treatment with the natural female sex hormone 17 beta-estradiol.
Hari Bhat, assistant professor of environmental health sciences, above, found estrogen only causes
cancer when cells also experience oxidative stress.
The cell uses a series of
reactions to rid itself of estrogen. In metabolizing carcinogenic estrogens, the reactions
produce intermediates capable
of producing oxygen radicals
that can damage the cell's fats,
proteins, and DNA. Unrepaired DNA damage can turn
into a mutation, which can
later promote cancer.
To see if cancer-causing
estrogens need oxygen radicals
to produce tumors, Bhat
implanted pellets of the hormone in hamsters that are susceptible to estrogen-induced
kidney cancer. This model is
widely used as an animal
model of hormonal cancer. As
expected, when the carcinogenic 17beta-estradiol (E2)
was used, nearly all hamsters
with the pellets developed cancer within seven months. E2
promotes cell proliferation and
produces oxygen radicals
when metabolized by the cell.
Also, as expected, none of
the hamsters developed kidney
cancer when a non-carcinogenic
estrogen, 17alphaethinylestradiol (EE) was
implanted. EE acts through
estrogen receptors to create
new cells like E2, but unlike
E2, is poorly broken down and
does not produce oxygen radicals.
But when EE was combined
with a non-estrogen molecule
that generates oxygen radicals,
30 percent of the hamsters
developed kidney cancer within seven months. The nonestrogen used, menadione, did
not produce tumors when used
alone.
"That we found tumors in the
EE plus menadione treated
hamsters clearly suggests that
estrogen receptor activity and
oxidative stress are both needed for estrogen to produce cancer," Bhat says. In other experiments, Bhat and his colleagues
confirmed that the oxidative
damage suffered by the cancer-
ous kidney cells was caused by
the metabolic breakdown of
E2. "That's why E2 acts as a
complete carcinogen," Bhat
says. "It's a potent estrogen
and it can also produce oxidative stress."
The more complete knowledge of how the estrogen
increases the risk of cancer
could lead to new anti-oxidant
therapies to treat or prevent
cancer.
But it also suggests that
reputedly "safe" estrogens that
are touted as replacements for
the estrogens in hormone
replacement therapy may not
be so safe after all. "If we have
oxidative stress in cells from
other chemicals, then women
are at risk for cancer even with
estrogens that are considered
non-carcinogenic," Bhat says.
"The therapy may be safer if
taken with antioxidants, but
more research is needed to
make safe and more effective
antioxidants."
Computer Scientist Julia Hirschberg Explores Frontiers of Computational Linguistics
BY JOSEPH KENNEDY
More than three decades
ago, the film 2001: A Space
Odyssey introduced audiences
to a chillingly malevolent
supercomputer named HAL.
In what was then the far-off
future, the film imagined
machines that could speak
and understand human speech
(and even read lips!). HAL
became an instant symbol for
the dangers of runaway technology.
While artificial intelligence
researchers have managed
thus far to avoid creating
monsters like HAL, the idea
of humans and computers
speaking to each other is no
longer the stuff of science
fiction. It is instead the driving force behind the grow-
ing discipline of computational linguistics, which studies
the computational aspects of
human language.
“Basic speech recognition
systems have now become
commonplace,” says Julia
Hirschberg, who joined the
Department of Computer Science
in
Fall
2002.
“Researchers today are moving into some very interesting
and complex areas. We’re
looking at how to enable computers to recognize speech
errors, perform audio browsing and retrieval of email, and
recognize and produce emotional speech.”
Hirschberg received a Ph.D.
in computer science from the
University of Pennsylvania in
1985. That same year, she
began working in the linguistics research department at
Julia Hirschberg
AT&T Bell Laboratories. In
1996 she moved to AT&T
Labs – Research, specializing
in human-computer interface
research.
Hirschberg is part of a
Columbia team researching
speech summarization, an
area of natural language pro-
cessing that enables systems
to summarize spoken words.
The Columbia Natural Language Processing Group,
headed by Kathy McKeown,
obtained an NSF and a
DARPA grant for research in
this area.
“We want to learn what
speech cues will lead a system to understand what is
important to summarize,”
Hirschberg says. “Although
a lot of research has been
done on text summarization,
not too many people are trying to produce spoken summaries. It could lead to applications that summarize things
like news broadcasts or voice
mail messages in spoken
form.”
Another
focus
of
Hirschberg’s research at
Columbia
is
emotional
speech. Computer scientists
are studying this process
from the perspectives of
speech recognition as well as
speech generation.
“There is an effort underway to enable computers to
recognize emotions in human
speech,” she said. “Work is
also being done to help computers generate emotional
speech. Both of these would
have enormous potential for
commercial applications.”
Applications might include
a tutorial system that could
recognize confidence, or the
lack thereof, in a student, and
customize its lessons accordingly.
On the generation
side, text-to-speech systems
that speak emotionally could
have a number of consumer
uses, from books for the
blind to to computer games.