Estrogen Metabolism and Breast Cancer

Abstract

Oxidative metabolites of estrogens have been implicated in the development of breast cancer, yet relatively little is known about the metabolism of estrogens in the normal breast. We developed an experimental in vitro model of mammary estrogen metabolism in which we combined purified, recombinant phase I enzymes CYP1A1 and CYP1B1 with the phase II enzymes COMT and GSTP1 to determine how 17β-estradiol (E2) is metabolized. We employed both gas and liquid chromatography with mass spectrometry to measure the parent hormone E2 as well as eight metabolites, that is, the catechol estrogens, methoxyestrogens, and estrogen–GSH conjugates. We used these experimental data to develop an in silico model, which allowed the kinetic simulation of converting E2 into eight metabolites. The simulations showed excellent agreement with experimental results and provided a quantitative assessment of the metabolic interactions. Using rate constants of genetic variants of CYP1A1, CYP1B1, and COMT, the model further allowed examination of the kinetic impact of enzyme polymorphisms on the entire metabolic pathway, including the identification of those haplotypes producing the largest amounts of catechols and quinones. Application of the model to a breast cancer case-control population defined the estrogen quinone E2-3,4-Q as a potential risk factor and identified a subset of women with an increased risk of breast cancer based on their enzyme haplotypes and consequent E2-3,4-Q production. Our in silico model integrates diverse types of data and offers the exciting opportunity for researchers to combine metabolic and genetic data in assessing estrogenic exposure in relation to breast cancer risk.

A novel GC-MS method in urinary estrogen analysis from postmenopausal women with osteoporosis

“…Both compounds have similar molecular weight and mass fragments. In general, 16 ␣ -OH-E1 stimulated cell proliferation in breast cancer cell lines and showed estrogenic and genotoxic potential in oxidative stress-induced biological actions ( 40 ). Accurate quantifi cation is very important, and EOC-PFP derivatization gave selective and sensitive detection in urine samples.…”

Preferential Induction of CYP1A1 over CYP1B1 in Human Breast Cancer MCF-7 Cells after Exposure to Berberine

“…Accumulative evidences suggest that estrogen-induced carcinogenesis depends on estrogen metabolism. Hydroxylation, which is the first step in the metabolism of estrogens, is initiated by CYP enzymes, especially CYP1A1 and CYP1B1 (Parl et al, 2009). CYP1A1 generates primarily 2-OH E 2 , which is less toxic and has been considered as protective (Spink et al, 1992;Schumacher et al, 1999).…”

“…In breast epithelium, the production of estrogen catechols depends on the activity of enzymes, especially CYP1A1 and CYP1B1 (Badawi et al, 2001;Parl et al, 2009). CYP1A1 displays hydroxylase activity at the C2 position to form 2-OH E 2 metabolite, whereas CYP1B1 displays its primarily activity on the C4 position to produce 4-OH E 2 metabolite (Spink et al, 1992;Hayes et al, 1996).…”

“…17β-estradiol (E 2 ), the main estrogen in the breast, can be metabolically transformed to 2-OH E 2 and 4-OH E 2 (Parl et al, 2009). The catechols 2-OH E 2 and 4-OH E 2 can be oxidized to quinones (Cavalieri et al, 1997).…”

Combined Docking and Quantum Chemical Study on CYP-Mediated Metabolism of Estrogens in Man

“…Recently, estradiol-3,4-quinone was identified as a potential risk factor in breast cancer, 23 and it was shown to form a quinone-DNA adduct thereby causing mutations and initiating carcinogenesis.…”