A collaborative study conducted at the Frederick National Lab and published in Cancer Research has provided new insight as to why elevated estrogen levels are associated with an increased risk of breast cancer.
Scientists have traditionally agreed that there is a link between high endogenous estrogen levels in postmenopausal women and a high risk of developing breast cancer. However, for many years, they’ve debated why the connection exists.
Recently, a team of researchers led by Joshua N. Sampson, Ph.D., and Gretchen L. Gierach, Ph.D., senior investigators, Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), evaluated data from four studies of breast cancer risk in postmenopausal women previously conducted in collaboration with the Frederick National Lab and uncovered new insights into two competing hypotheses.
Estrogens can be hydroxylated and metabolized at different carbon positions of the steroid ring. According to one theory, the 16-hydroxylation metabolites attach themselves to estrogen receptors, resulting in increased cell proliferation, which in turn gives the body more opportunities to develop carcinogenic cells. The other theory asserts that 2- and 4-hydroxylation catechol estrogen metabolites can become mutagenic compounds that damage DNA and enable the development of cancer.
Until recently, technological limitations made it difficult to establish strong evidence in human populations in favor of either theory, but Sampson and colleagues had a newer method at their disposal: a sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay developed in collaboration with NCI at Frederick that allowed them to document more reliable results.
Although the findings require more exploration, they indicate that, for participants with similar total estrogen levels, those with higher relative levels of 16-hydroxylation metabolites as compared to 2-hydroxylation metabolites were at a significantly increased risk of breast cancer. This conclusion appears to support the first hypothesis, indicating that estrogen-stimulated cell proliferation may be a major culprit in the formation of breast cancer in postmenopausal women. The results also seem to challenge the second hypothesis, since the proposed mutagenic effects of the 4-hydroxylation metabolites couldn’t be confirmed.
But the team didn’t just clarify the ongoing debate—they found suggestive evidence that, for women with similar total estrogen levels, a lower Body Mass Index was associated with lower levels of 16-hydoxylation metabolites. That could mean eating a healthy diet and increasing exercise may have the potential to reduce breast risk cancer risk. If further investigation can find interventions, even as mundane as increased physical activity, that are associated with higher levels of estrogen being pushed through the 2-hydroxylation pathways, then simple lifestyle changes might lower breast cancer risk.
“The hope is that this fundamental knowledge will eventually allow us to propose interventions that can reduce the risk of breast cancer,” said Sampson. While they require more study, lifestyle alterations appear to be one of the most promising ways to do so.
Gierach, the study’s senior author, agrees with Sampson’s evaluation. “We have previously found estrogen metabolites to be related to objectively measured physical activity and sedentary behavior, which we have also shown to be associated with breast cancer risk,” she said.
Xia Xu, Ph.D., senior scientist, Hormone Analysis Unit, Cancer Research Technology Program, Leidos Biomedical Research Inc., was one of the leaders in developing the innovative LC-MS/MS method to measure these metabolites, and he also participated in the analysis. He noted that the results “confirmed an important piece in the postmenopausal breast cancer puzzle, which could help its prevention effort.”
Sampson received a Ph.D. in biostatistics from the University of Washington and completed a postdoctoral fellowship in statistical genetics at Yale University. He has worked at NCI at Frederick for nearly eight years and says his desire to study biostatistics stems from his curiosity about the molecular etiology of cancer. Currently, he is working to develop methods to identify molecular mediators that link risk factors to breast cancer.
Gierach completed her graduate work at the University of Pittsburgh Graduate School of Health, where she focused on cancer epidemiology and women’s health. She decided to specialize in breast cancer epidemiology because she hoped that her research would lead to the development of improved detection, prevention, and treatment methods. She joined the DCEG in June 2006. Her current work involves conducting integrative molecular epidemiologic research on breast cancer, especially by examining breast density and hormones as risk factors for sporadic breast cancer among women.
Xu received his medical degree from Shanghai Jiao Tong University School of Medicine, Shanghai, China, and his Ph.D. in toxicology from Iowa State University, Ames, Iowa. He completed his postdoctoral training in nutrition and endocrinology at the University of Minnesota Twin Cities, Minnesota, studying human endogenous estrogen metabolism via chromatography-mass spectrometry–based methods. He also received post-doctoral cancer epidemiology training at DCEG. Working with DCEG investigators, he has developed several targeted metabolomics LC-MS/MS assays for quantitatively measuring human endogenous hormones (such as estrogens, androgens, and progesterones) and their metabolic profiles in large cancer epidemiology studies. He and his unit will continue supporting DCEG’s hormone analysis efforts.