Differences in Estrogen Metabolism May Influence Breast Cancer Risk ► NCI Cancer Bulletin for January 24, 2012 - National Cancer Institute

NCI Cancer Bulletin for January 24, 2012 - National Cancer Institute

Differences in Estrogen Metabolism May Influence Breast Cancer Risk

The way a woman’s body processes, or metabolizes, the hormone estrogen may influence her risk of postmenopausal breast cancer, according to new data from NCI’s Division of Cancer Epidemiology and Genetics (DCEG) published online January 9 in the Journal of the National Cancer Institute.

In postmenopausal women, higher levels of estrogen are known to be associated with an increased risk of breast cancer. Laboratory work, however, has suggested that how estrogen is metabolized may also be important for risk. Two major hypotheses for the role of estrogen metabolites have dominated the field: one, that specific metabolites stimulate tumor growth and progression; and two, that specific metabolites function as mutagens and initiate DNA damage that can turn a normal cell into a cancerous one. This study confirms that estrogen metabolism is important and lends credence to both hypotheses.

“Those are the results we’re most excited about and also the most cautious about, because it’s the first time that we’ve been able to measure the relevant metabolites in blood in an epidemiologic setting,” said Dr. Barbara Fuhrman, a postdoctoral fellow with DCEG and lead author of the study. She and her colleagues used a novel liquid chromatography/mass spectrometry assay that allowed them to measure 15 different parent estrogens and estrogen metabolites accurately at the very low concentrations present in postmenopausal women.

They performed their analyses on blood samples taken from women enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Researchers compared the blood samples of 277 postmenopausal women who later developed breast cancer and 423 matched women without the disease. None of the women were taking menopausal hormone therapy at the time of blood collection.

Apart from the expected strong relationship with estradiol, the researchers found no clear relationships between individual hormone and metabolite concentrations and cancer risk. When they considered relationships among the three major estrogen metabolic pathways and their components, the clearest patterns emerged when they compared the pathways to one another and to the total pool of parent estrogens available for metabolism. Two metabolic patterns seemed to influence breast cancer risk in a statistically significant manner independent of circulating estradiol. One pattern was associated with an increased risk of breast cancer, whereas the other was associated with a decreased risk. When the researchers included a measure of each of these patterns in an established risk prediction model for breast cancer, the calculated risk for a considerable number of the women changed substantially.

“Although these findings are of great research interest, they need to be replicated and there are no immediate clinical implications,” said Dr. Regina Ziegler, also of DCEG and the senior author on the study. “We are still at the beginning of our understanding of the complex role of estrogen in the etiology of breast cancer. By improving our knowledge of the role of estrogen metabolism, we may uncover novel strategies for chemoprevention and treatment and be better able to predict an individual’s risk of breast cancer.”