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Evidence at Molecular Level Supports Link Between Environmental Estrogens and Breast Cancer

Evidence at Molecular Level Supports Link Between Environmental Estrogens and Breast Cancer

Data from two studies presented at the 88th Annual Meeting of the American Association for Cancer Research (AACR) have added evidence to support an association between environmental estrogens and breast cancer. Lifetime exposure to endogenous estrogens is known to be a risk factor for breast cancer. However, there is uncertainty about whether environmental estrogens such as DDT are definitively linked to breast cancer. Two large epidemiological studies conducted in the 1990s produced conflicting findings regarding the correlation between increasing concentrations of DDT metabolites and incidence of breast cancer. Moreover, little is known about the potential mechanisms by which endogenous or environmental estrogens convert normal breast epithelial cells into abnormal cells.

Scientists from the Karmanos Cancer Institute in Detroit examined the effects of estradiol and five closely related organochlorine pesticides on cell growth in two estrogen receptor-positive human breast epithelial cell lines: precancerous cells and human breast cancer cells. Organochlorine pesticides have been associated with the development of breast cancer because of their estrogenic properties. Those selected for this study act as estrogens with actions mediated through the estrogen receptor.

Pesticide Combinations More Lethal

Using a special assay, the investigators found that when the pesticides were administered individually, they caused the human breast epithelial cells to proliferate, but only when they were administered at 100- to 1,000-fold higher levels than estradiol. However, when the pesticides were administered in combination, they caused cell proliferation similar to that observed with physiological concentrations of estradiol.

According to study investigator, Malathy Shekhar, PhD, "To date, there is no conclusive proof that endogenous estrogens cause breast cancer. The only evidence comes from epidemiological studies showing an association between an individual's total cumulative exposure to estrogen and breast cancer. In order to provide stronger evidence for this association, we studied the possible mechanisms by which estrogens cause malignancy. We used an estrogen receptor-positive precancerous cell line that we developed."

Dr. Shekhar added, "We found that estradiol and the pesticides activated estrogen-mediated responses via estrogen receptors on this cell line, suggesting that some environmental estrogens, particularly in combination, may be involved in breast cancer progression. This is an important finding because environmental estrogens such as DDT still pose a threat to humans even though their use has been banned for many years. Not only does DDT remain in the environment for many years, but it also concentrates in adipose tissue in the breast and other organs in the body."

In a second study reported at the AACR Annual Meeting, researchers at the University of Rochester School of Medicine and Dentistry investigated whether DDT isomers, different chemical forms of DDT, and their metabolites can bind to and activate estrogen receptors in humans and act as estrogens. Results from previous studies had indicated that certain DDT compounds specifically bind to and activate rodent and avian estrogen receptors, but no data have been available on how these compounds interact with the human estrogen receptor at the molecular level.

Rat vs Human Receptors

Experiments conducted by researchers at the University of Rochester School of Medicine and Dentistry measured the ability of DDT isomers and metabolites to bind to and activate the human estrogen receptor. The studies found that many of the DDT compounds had more than 100-fold higher affinities for the human estrogen receptor than for the rat estrogen receptor. Using a cellular model that expresses human estrogen receptors and provides a measurable signal when this receptor is activated, the researchers screened the DDT compounds for estrogenic activity. They found that the DDT isomers and metabolites that bound to the human estrogen receptor were able to activate it in a concentration-dependent manner and elicit an additive response when administered with another DDT metabolite or with estradiol.

According to study investigator, Clarice W. Chen, MS, "Of particular significance is the finding that both DDT isomers bind to the human estrogen receptor, whereas only one binds with measurable affinity to the rat estrogen receptor. Moreover, many DDT metabolites have a substantially higher affinity for the human than the rat estrogen receptor, even though the main metabolite of DDT does not. Our data suggest the metabolites that activate the human estrogen receptor do so with the same potency as the parent compounds, and this activation is additive to that of another DDT compound or estradiol. These findings differ from those using other animal models and suggest that humans may be more susceptible to DDT metabolites than other species."

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