Estrogen Metabolism and Exposure in a Genotypic–Phenotypic Model for Breast Cancer Risk Prediction

Abstract

Background Current models of breast cancer risk prediction do not directly reflect mammary estrogen metabolism or genetic variability in exposure to carcinogenic estrogen metabolites. Methods We developed a model that simulates the kinetic effect of genetic variants of the enzymes CYP1A1, CYP1B1, and COMT on the production of the main carcinogenic estrogen metabolite, 4-hydroxyestradiol (4-OHE2), expressed as area under the curve metric (4-OHE2-AUC). The model also incorporates phenotypic factors (age, body mass index, hormone replacement therapy, oral contraceptives, family history), which plausibly influence estrogen metabolism and the production of 4-OHE2. We applied the model to two independent, population-based breast cancer case-control groups, the German GENICA study (967 cases, 971 controls) and the Nashville Breast Cohort (NBC; 465 cases, 885 controls). Results In the GENICA study, premenopausal women at the 90th percentile of 4-OHE2-AUC among control subjects had a risk of breast cancer that was 2.30 times that of women at the 10th control 4-OHE2-AUC percentile (95% CI 1.7 – 3.2, P = 2.9 × 10−7). This relative risk was 1.89 (95% CI 1.5 – 2.4, P = 2.2 × 10−8) in postmenopausal women. In the NBC, this relative risk in postmenopausal women was 1.81 (95% CI 1.3 – 2.6, P = 7.6 × 10−4), which increased to 1.83 (95% CI 1.4 – 2.3, P = 9.5 × 10−7) when a history of proliferative breast disease was included in the model. Conclusions The model combines genotypic and phenotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure to predict breast cancer risk. Impact The estrogen carcinogenesis-based model has the potential to provide personalized risk estimates.

Dual roles of estrogen metabolism in mammary carcinogenesis

“…It is, therefore, necessary to develop a refined model that utilizes a pathway-based functional and quantitative approach. The most recent risk prediction model proposed by Parl and his colleagues is developed to incorporate estrogen exposure parameters, individual phenotypic factors such as body mass index or family history, and the functional effects of genetic variants of CYP1A1, CYP1B1, and COMT (29,109). Consideration of phenotypic factors and genetic polymorphism will allow researchers to predict the exposure to carcinogenic catechol estrogen metabolites at more accurate and quantitative levels in this novel genotypic-phenotypic model.…”

“…As the recent research results define the estrogens and its metabolites as a prime breast cancer risk, prediction models for breast cancer risks have been developed on the basis of estrogen exposure as well as estrogen metabolism and metabolizing enzyme variants. For a more precise and individualized prediction, the kinetic effects of genetic variants of the major estrogen metabolizing enzymes are taken into account in the recent prediction model (28,29). In this review, the roles of estrogens and their metabolites in mammary carcinogenesis will be discussed.…”

Estrogen Receptor Alpha Gene Polymorphisms and Breast Cancer Risk: a Case-control Study with Meta-analysis Combined

“…Cumulative, excessive estrogen exposure from both endogenous and exogenous sources can lead to pathological consequences in multiple human tumors, including breast cancer (Crooke et al, 2011). Experiments have shown that estrogen is an important regulator of growth and differentiation in the normal mammary gland and is important in the development and progression of breast carcinoma (Medina et al, 2001).…”

Efectos del té verde sobre el riesgo de cáncer de mama

“…Más específicamente, se ha demostrado que niveles elevados de estrógenos 4 y 16-hidroxiestrógeno en sangre aumentan el riesgo de cáncer de mama al incrementar la tasa de división celular y tener efecto proliferativo sobre las células epiteliales mamarias [73][74][75] . El citocromo P450, concretamente los CYP 1B1, 1A1, 1A2 y 3A4 de la fase I del metabolismo hepático, producen la hidroxilación del estradiol y estrona convirtiéndolos en hidroxiestrógenos de efecto incrementado y con mayor afinidad sobre los receptores estrogénicos 76,77 . Esta activación ha sido estudiada por su efecto carcinogénico en diferentes cánceres, entre los que destacan el de mama 78 y endometrio 76,77 .…”

“…El citocromo P450, concretamente los CYP 1B1, 1A1, 1A2 y 3A4 de la fase I del metabolismo hepático, producen la hidroxilación del estradiol y estrona convirtiéndolos en hidroxiestrógenos de efecto incrementado y con mayor afinidad sobre los receptores estrogénicos 76,77 . Esta activación ha sido estudiada por su efecto carcinogénico en diferentes cánceres, entre los que destacan el de mama 78 y endometrio 76,77 . Los metabolitos estrogénicos como 4-hidroxiestradiol, 4-hidroxiestrona, 16-hidroxiestradiol, 4-hidroxi-catecol-estrógeno, etc.…”