Imbalances in the disposition of estrogen and naphthalene in breast cancer patients: a potential biomarker of breast cancer risk

Dar-Ren Chen,Yu-Fen Wang,Yi-Lun Liao,Wei-Chung Hsieh,Po-Hsiung Lin,Kuo-Juei Lin

doi:10.1038/s41598-020-68814-5

Abstract

Elevation of naphthoquinones and estrogen quinones, which are reactive metabolites of naphthalene and estrogen, is thought to be an important indicator of naphthalene- and estrogen-induced carcinogenesis. We compared background levels of naphthalene and estrogen quinone-derived adducts in serum albumin (Alb) from 143 women with breast cancer and 119 healthy controls. Cysteinyl adducts of naphthoquinones, including 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ), and estrogen quinones, including estrogen-2,3-quinones (E2-2,3-Q) and estrogen-3,4-quinones (E2-3,4-Q), were characterized after adduct cleavage. Levels of estrogen quinones and naphthoquinones were positively correlated in healthy controls, but not in breast cancer patients (p < 0.05). Compared with controls, levels of 1,2-NPQ and E2-3,4-Q were elevated by two- to ten-fold in cancer patients (p < 0.001). To explore the correlation between estrogen- and naphthalene-derived quinone adducts and disease status, we performed linear discriminant analysis of the ratio of 1,2-NPQ-Alb to (1,2-NPQ-Alb plus 1,4-NPQ-Alb) versus the ratio of E2-3,4-Q-2-S-Alb to (E2-2,3-Q-4-S-Alb plus E2-3,4-Q-2-S-Alb) in patients and controls. These two groups were separable using albumin adducts of estrogen quinones and naphthoquinones, with 99.6% overall correct classification rate (overall accuracy). The findings of this study suggest that differences in the disposition of estrogen and naphthalene, and the subsequent elevation of cumulative E2-3,4-Q and 1,2-NPQ may serve as biomarkers of breast cancer risk.

Highlights

Elevation of naphthoquinones and estrogen quinones, which are reactive metabolites of naphthalene and estrogen, is thought to be an important indicator of naphthalene- and estrogeninduced carcinogenesis
Albumin (Alb) adducts of quinonoid metabolites of naphthalene have been used as biomarkers of occupational and environmental exposure to Polycyclic aromatic hydrocarbons (PAHs), with increased naphthoquinone-derived Alb adduct levels detected in coke oven workers[33]
To extend our previous research on estrogen quinone adducts in serum Alb on a broader scale, we examined the relationships between body burden of estrogen quinones with naphthoquinones in serum derived from breast cancer patients and controls and performed correlation analysis of levels of estrogen and naphthalene-derived quinone adducts with disease status

Summary

Introduction

Elevation of naphthoquinones and estrogen quinones, which are reactive metabolites of naphthalene and estrogen, is thought to be an important indicator of naphthalene- and estrogeninduced carcinogenesis. Levels of estrogen quinones and naphthoquinones were positively correlated in healthy controls, but not in breast cancer patients (p < 0.05). Cytochrome P450 1A2 and 2D6 have been identified as the most active isoforms for the production of 1,4-naphthoquinone (1,4-NPQ) from 1-naphthol, which occurs via 1,4-naphthalenediol (NHQ)[24] This compound is thought to initiate cancer via the activation and interaction of 1,2-NPQ with DNA to form depurinating adducts[32]. To extend our previous research on estrogen quinone adducts in serum Alb on a broader scale, we examined the relationships between body burden of estrogen quinones with naphthoquinones in serum derived from breast cancer patients and controls and performed correlation analysis of levels of estrogen and naphthalene-derived quinone adducts with disease status. Products of reactions between estrogen quinones and Alb are designated as E2-2,3-Q-1-S-Alb, E2-2,3-Q-4-S-Alb, and E2-3,4-Q-2-S-Alb, respectively, and those with naphthoquinones as 1,2-NPQ-S-Alb and 1,4-NPQ-S-Alb, respectively

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