The Pathway of Estrogen Metabolism Affects Breast-Cancer Risk, UB Research Shows

BUFFALO, N.Y. -- Researchers at the University at Buffalo have found that the development of breast cancer appears to be related to how the body breaks down estrogen.

In only the second prospective study to investigate the role of estrogen metabolism as a predictor of breast cancer, the researchers found that premenopausal women show a 40-percent lower risk of the disease if their predominant pathway of estrogen metabolism produces by-products with little biologic activity, rather than by-products that are highly reactive.

Results of the study appear in the November issue of Epidemiology.

The research is based on data from 10,786 women who took part in a prospective study of breast cancer in Italy called the Hormones and Diet in the Etiology of Breast Cancer (ORDET) study. Paola Muti, M.D., now associate professor of social and preventive medicine at the University at Buffalo School of Medicine and Biomedical Sciences, was principal investigator on that study.

Estrogen must be eliminated from the body once it has performed its essential hormonal duties. High levels of estrogen are known to be a risk factor for cancer and too much also upsets the body's delicate hormonal balance. In order to be eliminated from the body, estrogen undergoes a process called hydroxylation. These hydroxilated estrogens, called estrogen metabolites, can travel easily in the blood stream and be eliminated through the urine.

"Estrogen hydroxylation takes place at two primary sites on the estrogen molecule, designated as the C-2 position and the C-16 position," Muti said. "Earlier research has shown that hydroxylation at the C-2 position produces metabolites with little or no estrogenic activity and thus might be associated with decreased breast-cancer risk. Conversely, hydroxylation at the C-16 position produces metabolites with high estrogenic activity, and might be associated with increased breast-cancer risk.

"We set out to determine if there was an association between later development of invasive breast cancer and the ratio of C-2 to C-16 by-products present in women before cancer developed."

Researchers collected urine samples from all participants when they enrolled in the study and froze them for later analysis. Women with a history of cancer and those with other relevant conditions had been eliminated from the study. After approximately five years, researchers determined that 144 women had developed breast cancer, and they selected four times that number of women from the study who had not developed cancer to serve as controls. Researchers then analyzed the urine samples from both cases and controls to determine the predominant estrogen-metabolism pathway.

Results showed that the premenopausal women who developed breast cancer had a higher percentage of the highly active by-products of estrogen metabolism (produced by the C-16 pathway), than by-products from the C-2 pathway. Women with predominately C-2 pathway by-products (those with low activity) were 40 percent less likely to have developed breast cancer during those five years.

"The way to change from one pathway to the other is through changes in lifestyle," said Muti. "Physical activity and eating a diet low in fat and high in cruciferous vegetables can shift estrogen metabolism from high-risk to low-risk."

Muti and colleagues will continue to investigate why one pathway increases breast-cancer risk and the other does not.

Also participating in the study were Jo L. Freudenheim, Ph.D., Holger Schunemann, M.D., Jun Yang, M.D., and Maurizio Trevisan, M.D., of the UB Department of Social and Preventive Medicine; H. Leon Bradlow, Ph.D., and Daniel W. Sepkovic, Ph.D., from Strang Cancer Research Laboratory in New York City; Andrea Micheli, Ph.D., Vittorio Krogh, M.D., and Franco Berrino, M.D., from the National Tumor Institute in Milan, Italy, and Martin Stanulla, M.D., from the Medical School of Hannover, Germany.