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When the Women's Health Initiative (WHI) halted its study on hormone replacement therapy last year because it found an increased risk of invasive breast cancer, some scientists were not at all surprised. For years, these researchers had been studying not if--but how--estrogens cause cancer. A few of them gathered in New York City last month at the American Chemical Society's national meeting to present their latest findings on the molecular mechanisms of estrogen carcinogenesis. Their reports support the theory that estrogen's chemical metabolites damage DNA. In addition, one study raises the possibility that some women are genetically more susceptible to that damage than others. "I have to go back to my wife and report on this," said Nicholas E. Geacintov, a professor of chemistry at New York University, shortly before the session. Lately, he said, she has not at all been pleased with the ability of doctors and scientists to tell her whether she should be taking hormone replacement therapy (HRT) or not. Smoller Bolton PHOTOS BY LOUISA DALTON Her frustration is understandable. In the past few years, the medical community has done an about-face with regard to HRT, said Sylvia Wassertheil-Smoller, a professor of epidemiology and population health at Albert Einstein College of Medicine, Yeshiva University, New York City. Before 1991, Smoller said, if a woman went to her doctor with symptoms of menopause, she might have been told any or all of the following: HRT will help relieve the symptoms of menopause, including hot flashes, sleeplessness, and mood swings; it will help bones stay strong; it will lower the risk of developing heart disease and colon cancer; and it may slow the process of cognitive decline. On the other hand, a woman was likely warned, it seems to increase slightly the risk of developing breast cancer and raises the incidence of venus thrombosis and pulmonary embolism. The evidence supporting these benefits and risks of HRT, Smoller said, came primarily from what she called "observational studies." Scientists observed that women who chose to take HRT had all of the above effects. Observational studies can be helpful, Smoller said, but they can also be misleading. It is difficult for a scientist conducting an observational study to factor out all confounding attributes. Those who choose to take HRT, Smoller said, are more likely to be active, to be highly educated, and to see their doctors, while being less likely to smoke or to be obese, and thus are generally healthier to begin with. A large-scale clinical trial was needed, Smoller said. In the 1990s, such a study was proposed as part of WHI, set up by the National Heart, Lung & Blood Institute of the National Institutes of Health. The goal of this mammoth initiative involving more than 160,000 women in 40 clinical centers was to study the health and quality of life in postmenopausal women. In one arm, 16,608 women were recruited for what was to be an eight- to 10-year clinical trial on the health effects of HRT among women who had an intact uterus. Smoller headed the WHI center in New York. Women in the study took either a placebo or a combination hormone therapy that contained conjugated equine estrogens (estrogen) and medroxyprogesterone acetate (progestin). This combination of female hormones--estrogen and progestin--is the most commonly prescribed HRT for women in the U.S. who have not had a hysterectomy. The treatment is a mix of compounds. Premarin and Prempro, manufactured by Wyeth-Ayerst Laboratories, contain estrogens extracted from pregnant mare's urine. About 40% of the estrogens are equilin and equilenin, which only differ from human estrogen (estradiol) by one or two double bonds, respectively. (The term "estrogen" can refer to any compound that activates estrogen receptors.) Just over five years into the study, the Data & Safety Monitoring Board that oversees the WHI trial cut the HRT arm short. In July 2002, WHI announced that the health risks of HRT outweigh its benefits, and the study participants would be asked to stop taking their study drugs. Specifically, those on HRT were found to be at increased risk for breast cancer (24% increased risk), heart disease (29%), stroke (31%), and pulmonary embolism (113%) [J. Am. Med. Assoc., 288, 321 (2002)]. (Note that those percentages are for increased risk and not for increased incidence.) Rogan Geacintov Yager THE BREAST CANCER results were particularly striking. Breast tumors found in women on HRT were larger and at a more advanced stage, and even in the first year of the trial, women on HRT had more abnormal mammograms than those on a placebo. Additionally, a memory study funded by Wyeth-Ayerst found that those on HRT had twice the risk of developing dementia compared to those on placebo. On the other hand, WHI administrators found that HRT still had significant benefits. Those taking estrogen plus progestin had stronger bones (34% decreased risk of hip fractures). And their risk of getting colon cancer decreased by 37%. "For the first time, we know the risks and benefits of long-term hormone therapy," Smoller said. Yet even though the WHI trial answered some questions, it left others open. Do the risks go away once a woman stops using HRT? Why does HRT decrease the risk of getting colon cancer and have the opposite effect for breast cancer? Are there certain groups of women more susceptible to the risks of HRT? "It may be," Smoller said, "that those who are susceptible succumbed right away. And those who have taken HRT for 30 years with no adverse effects could take it safely for another 30." However, who that might be is unknown, and "women should not start or continue on HRT in order to prevent heart disease, cancer, or dementia," Smoller asserted. Delving into how estrogen works in the body will help answer some of the outstanding questions from the WHI study. Judy L. Bolton, organizer of the ACS symposium and professor of medicinal chemistry and pharmacognosy at the University of Illinois, Chicago, believes that understanding how estrogen induces cancer at the molecular level will eventually lead to more informed guidance for women. Estrogens play many roles in the body, but they have two distinct effects that can contribute to cancer, Bolton pointed out. First, estrogens are hormones. They bind to estrogen receptors and set off a cascade of normal estrogenic tasks. One of these is increased cell proliferation, particularly in the breast and endometrium. And cell proliferation, even for necessary functions like menstruation and breast-feeding, sometimes leads to cancer. For many years, this was thought to be the primary route of estrogen carcinogenesis. But a number of researchers, including the late Joachim G. Liehr, formerly chief pharmacologist at the Stehlin Foundation for Cancer Research in Houston, established that estrogens contribute to cancer in one other major way. "Estrogens are also chemicals," Bolton said. In other words, the body metabolizes estrogens as it does other chemical compounds. A concentration of studies in the past 10 to 15 years has established that estrogens are transformed by the cell into more reactive metabolites that can bind to DNA and can cause oxidative damage to DNA, lipids, and proteins. The products of these reactions disturb fundamental cellular functions, such as replication and cell division, making it more likely that a cell will become cancerous. Almost all estrogens go through two general processing phases in a woman's body. In phase I, estradiol (or the HRT drugs equilin or equilenin) is oxidized by a P450 enzyme. Depending on the P450 that does the oxidizing, the tissue type, and other factors, this leads to reactive metabolites, including 16--hydroxy, 2-hydroxy, and 4-hydroxy estrogens. In phase II, those reactive metabolites are converted into inactive, easily excretable forms by the enzyme catechol-O-methyltransferase (COMT). It's those intermediates, chemically reactive metabolites that are the troublemakers. Not only are they themselves reactive, but the 2-hydroxy and 4-hydroxy forms oxidize easily to their semiquinone and o-quinone forms, which also cause damage to DNA. The laboratories of Bolton, Geacintov, and Eleanor G. Rogan at the University of Nebraska Medical Center have been working on tracing the DNA-damaging effects of many of these phase I products. Rogan's research, done mainly on mouse skin and rat mammary glands, focused on metabolites of estradiol and estrone, another estrogen. Her results suggest that one metabolite in particular--estrogen-3,4-quinone--depurinates DNA. The 3,4-quinone binds to the nucleic acid bases adenine and guanine, forming products that are unstable and dissociate from the DNA backbone. The resulting apurinic site in the DNA sequence is often fixed by DNA repair enzymes incorrectly. ROGAN AND HER colleagues also carried out an illuminating study with human breast tissue. She looked at the concentrations of the three primary metabolites of phase I processing--16--hydroxy-, 2-hydroxy-, and 4-hydroxyestrogens--in breast tissue of women with cancer and those without. She found that the cancer tissue had significantly more of 4-hydroxyestrogens and estrogen-3,4-quinones than normal tissue did. Geacintov and Bolton collaborated in studying the DNA binding of the reactive metabolites formed from the HRT estrogens equilin and equilenin. Bolton's previous research revealed that equilenin's 4-hydroxy metabolite, 4-OHEN, also binds to DNA and forms stable adducts. Furthermore, her group showed that in rats, 4-OHEN causes a variety of damage to DNA including oxidation of DNA bases, DNA strand breaks, and formation of stable DNA adducts, as well as apurinic sites. Geacintov's group synthesized stereoisomers of the 4-OHEN-induced cytosine adduct and found that these adducts blocked the cytosine's ability to hydrogen bond with the opposite strand. These bulky adducts significantly destabilized double-stranded DNA and are expected to block DNA replication or cause mutations in cells. Rogan's, Bolton's, and Geacintov's work point to specific estrogen metabolites as possible instigators of cancer in breast tissue. Recent work by James D. Yager, a toxicologist at Johns Hopkins Bloomberg School of Public Health, investigates the role of the enzymes that do the metabolizing. Yager has focused on COMT, an enzyme at the tail end of estrogen metabolism. COMT adds a methyl group to the reactive estrogen metabolites 2- and 4-hydroxyestrogens. This inactivates the compounds and prevents them from being further metabolized to forms that can cause DNA damage. There are two forms of COMT--a high-activity and a low-activity form--and they differ by one amino acid. About a quarter of North American Caucasians are genetically homozygous for the low-activity allele, which means they cannot make any of the high-activity form. In tissues of these women, COMT activity is one-third to one-fourth that in women genetically homozygous for the high-activity allele. So a woman who produces only the low-activity form may be more exposed, for a longer time, to estrogen's reactive metabolites. Recently, Yager and former graduate student Jackie A. Lavigne, now at the National Cancer Institute, established that in cultured cells, the more active COMT is, the less estrogen-induced DNA oxidative damage occurs. In a recent collaboration, Yager, Bolton, and graduate student Yan Li found that 4-OHEN inhibits COMT and inhibits the low-activity COMT better than it inhibits high-activity COMT. Thus, a woman with the low-activity COMT may be even more at risk when taking Premarin. This work supports Smoller's guess that some subgroups of women may be more susceptible to developing breast cancer while on HRT than others. If true, it adds another layer of complexity to the mechanism of estrogen carcinogenesis. And it would add one more factor for women to consider as they weigh the risks and benefits of estrogen replacement. 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