Re: Coffee drinking and risk of endometrial cancer—A population‐based cohort study

Dear Editor, Friberg et al. present data from a large cohort of Swedish females that demonstrate a significant, inverse association between coffee consumption and risk of endometrial cancer. This finding corroborates the results from a recent prospective study conducted in Japan that also reported an inverse relationship between coffee drinking and endometrial cancer. The authors propose that coffee consumption improves insulin sensitivity, and thus reduces circulating insulin levels, which have been positively associated with endometrial cancer risk, and also lowers circulating free estradiol levels via up-regulation of sex hormone binding globulin synthesis. The biologic mechanism proposed by the authors is plausible and well-supported by both laboratory and observational data; however, I would like to suggest a separate mechanism that points to a more direct, estrogen-related pathway. In addition to the current data for coffee, there are other lifestyle and dietary factors that have been inversely linked to endometrial cancer risk. Most notably, several prospective investigations have reported that cigarette smoking is protective against endometrial cancer, a finding that has been attributed to possible anti-estrogenic effects of tobacco smoke. In addition, a recent large, prospective study on meat consumption and cancer that included 1,185 endometrial cancer cases, reported a statistically significant 25% reduction in endometrial cancer risk for women in the highest quintile of red meat consumption versus those in the lowest quintile. I believe that the results of the current study on coffee drinking and endometrial cancer risk, when considered alongside the data on tobacco smoking and red meat consumption, point to a biologic pathway that may be particularly relevant to endometrial carcinogenesis. A common feature of coffee, tobacco smoke and red meat, is the presence of bioactive compounds known to induce elements of cytochrome P450 metabolism. Specifically, the caffeine present in coffee can up-regulate hepatic expression of CYP1A2, while polycyclic aromatic hydrocarbons, heterocyclic amines and N-nitroso compounds found in tobacco smoke and cooked red meat can stimulate synthesis of CYP1A1, CYP1A2, CYP3A4 and CYP1B1. Interestingly, all of these enzymes play important roles in estrogen metabolism. Estradiol is a substrate for CYP1A1, CYP1A2 and CYP3A4, which catalyze its oxidation to 2-hydroxyestradiol. Subsequent methylation of 2-hydroxyestradiol can yield 2-methoxyestradiol, a metabolite with known anti-tumorigenic properties. The overall effect of these metabolic reactions is clearance of estradiol, or even the synthesis of metabolites that may have anti-proliferative effects on endometrial cells,though it has been noted that CYP1B1 activity can, under certain circumstances, lead to the production of superoxide intermediates. The inverse associations observed for coffee, tobacco smoke and red meat on endometrial cancer risk, if real, may be a consequence of the up-regulation of cytochrome P450-mediated metabolic pathways of estradiol. The enzymes that comprise this metabolic pathway may warrant particular attention for endometrial cancer chemoprevention strategies.