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 CE-quinone, 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.
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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 canceralbeit 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.
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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."
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