Estrogens Role in Cancer

It'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 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, Dr. Hari Bhat,
assistant professor of environmental health sciences. Their results suggest that blocking the
second pathway could prevent estrogen-induced cancers. But they also suggest that even noncarcinogenic 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," Dr. 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 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, Dr. 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, 17alpha-ethinylestradiol (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 non-estrogen
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," Dr. Bhat says.
In other experiments, Dr. Bhat and his colleagues confirmed that the oxidative damage
suffered by the cancerous kidney cells was caused by the metabolic breakdown of E2. "That's
why E2 acts as a complete carcinogen," Dr. 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," Dr. Bhat says. "The therapy may be safer if taken with
antioxidants, but more research is needed to make safe and more effective antioxidants."

Estrogen and DNA Damage: The Silent Source of

Breast Cancer?
In December, the hormone estrogen was declared a known human carcinogen by the National
Toxicology Program. The association between estrogen and cancer is nothing new; the
relationship between estrogen-driven cell proliferation and uterine cancer is well known, and
women with higher lifelong exposure to estrogen (resulting from early menses and late
menarche) have an elevated risk of breast cancer. But now that estrogen appears in the Tenth
Report on Carcinogens, the question has turned from whether estrogen causes cancer to how
it causes cells to become malignant.
One group of scientists thinks that there is more to estrogens cancer-causing properties than
most researchers believe. This rebellious group has long seen estrogen metabolites as cancer
initiators. It has been an uphill battle to convince the mainstream that estrogen initiates
cancer by damaging DNA, said David Longfellow, Ph.D., chief of the Chemical and
Physical Carcinogenesis Branch at the National Cancer Institute. These researchers come
from a new paradigm, he said. Mainstream medicine has been on a different vector.
According to the standard paradigm, estrogen promotes cancer by signaling cells to grow and
divide. When this message reaches cells with genetic mutations that could become malignant,
it triggers them to multiply out of control and form cancerous tumors. But estrogens
hormonal powers are not what cause cells to develop mutations in the first place, according to
this theory.
Thats where estrogens metabolites come in, said Longfellow. When estrogen is
metabolized, you can get a product that does damage to DNA in a manner very likely to cause
cancer. The research sends a consistent message, he said: Mammalian cells convert estrogen
into related compounds that not only generate free radicals capable of damaging DNA, but
also bind to DNA and pull out a nucleotide basea process known as depurination. The
resulting mutations can convert an innocent cell into a cancerous tumor.
One particular estrogen metabolite likely initiates many mutations that lead to breast and
uterine cancer, said Ercole Cavalieri, D.Sc., an environmental toxicologist at the University
of Nebraska Medical Center, Omaha. This prime suspect can steal bases from DNA at
remarkable speed. The perpetrator : a catechol estrogen quinone (CE-quinone) derived from
4-hydroxy catechol estrogen (4-OHE) and produced three metabolic steps away from
estrogen itself. Although our bodies know how to replace the DNA bases kicked out by CEquinone, Cavalieri said, The repair process is error prone because the reaction is so quick.
The wrong base is inserted instead of the right one, and thats how you get a mutation that
leads to cancer.
Some of the earliest studies of estrogens DNA-damaging potential came from the laboratory
of Joachim Liehr, Ph.D., a cancer researcher at the Stehlin Foundation for Cancer Research,
Houston. He worked with male Syrian hamsters, all of which develop kidney cancer when
treated with natural estrogen (17-estradiol). It turns out that the kidney is the primary
hamster organ that makes 4-OHEthe first estrogen metabolite along the path toward the
DNA-damaging CE-quinone. Treatment with 4-OHE induced kidney cancer in hamsters at

the same rate as estrogen treatment itself. These experiments suggest that 4-OHE and its
derivatives might be responsible for causing kidney cancer in hamsters.
Liehr and his colleagues also observed that, well before tumors appear, hamster kidney cells
exhibit signs of DNA damage from free radicals. Estrogen metabolism generates free radicals
in the same step that produces CE-quinones, so free radical damage to hamster DNA signals
the presence of these quinones. Free radicals might also contribute substantially to estrogens
potency as a cancer initiator.
In people, as in animal models, estrogen-related cancer occurs in precisely those tissues
(uterus and breast) that manufacture substantial amounts of the enzymes responsible for
turning estrogen into 4-OHE. Moreover, like in the hamster kidney, normal tissue
surrounding human breast tumors exhibits free radical DNA damage.
But the presence of 4-OHE and free radical damage in cancer-susceptible tissue also
coincides with the presence of the estrogen receptorthe molecule that allows estrogen to
promote cancer by boosting cell growth. To determine whether 4-OHE and its derivatives are
really cancer-causing villains, researchers needed to rule out the commonly held belief that
estrogen only increases breast and uterine cancer risks through hormonal action.
A key study that identified estrogens separate hormonal and DNA-damaging effects was
reported in 1999 by Ken Korach, Ph.D., and his colleagues at the National Institute of
Environmental Health Sciences. These researchers crossed mice genetically predisposed to
develop mammary cancer (Wnt-1 mice) with mice that lacked the ability to respond to
hormonal estrogen (estrogen receptor knockout mice). The animals still contracted cancer
albeit at a slower rateand when their ovaries were removed (depriving the animals of
estrogen) the incidence of cancer declined further. The results suggest that estrogen promotes
cancer by a means other than hormonal signaling.
In another key study, human breast epithelial cells lacking the estrogen receptor became
cancerous after estrogen treatments. And the cells accrued genomic changes like those seen in
several specific types of breast cancer.
Even knowing that estrogen causes cancer by nonhormonal means in mice and cell culture
left an important gap in the research. We need to cement the connection between the
metabolites and the cancer, said James D. Yager Jr., Ph.D., of Johns Hopkins University.
The first such connection came from a study described by Eleanor Rogan, Ph.D., an
analytical chemist at the University of Nebraska, and colleagues at the San Antonio Breast
Cancer Symposium in December 2002. They showed that women with breast cancer produce
elevated levels of the primary villainCE-quinonethan women without cancer. According
to Liehr, These findings provide some of the strongest support yet for the claim that an
imbalance in estrogen metabolites may indeed cause breast cancer in women.
With the U.S. government declaring estrogen a human carcinogen, the work of Cavalieri,
Rogan, and Liehr continues apace. They hope to develop drugs or nutritional supplements
that will prevent estrogens genotoxic effects.
And in October 2002, Cavalieri launched animal studies seeking to prevent the estrogen
imbalances that might lead to cancer. Knowing the origin of the problem makes it easier to

fix, he said. By stopping the quinones, we hope to reduce the chances of cancer
dramatically.
The researchers are hopeful that their work will lead to new preventive treatments with fewer
side effects than current approaches. Tamoxifen, the primary drug used for breast cancer
prevention today, blocks estrogens ability to promote breast cancer hormonally. It also puts
women into early menopause and increases their risk of uterine cancer and stroke.
Cavalieris research provides new drug targets that could aid womens health without
depriving them of estrogens beneficial effects, said Thomas Sutter, Ph.D., a genomics
researcher at the University of Memphis.
V. Craig Jordan, Ph.D., D.Sc., of Northwestern University, Chicago, the man who pioneered
tamoxifens use, agreed. This research has been in left field for about two decades. I think
we should give it a good bash for 5 years and see what happens.