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      Urinary estrogen metabolites and breast cancer risk in Chinese population

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          Abstract

          Background

          In China, the association between estrogen metabolism and breast cancer risk and the differences in metabolic pattern between breast cancer patients and controls are poorly understood.

          Methods

          A total of 84 patients with invasive breast cancer and 47 controls with benign breast diseases were included in this study. Estrogen metabolites from their morning urine were determined by HPLC-MS/MS and evaluated in both groups, and the predictive value of each estrogen metabolite in the malignant group according to their menstrual status was analyzed.

          Results

          Urinary concentration of estrogen metabolites 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 4-methoxyestrone (4-MeOE1), and 16α-hydroxyestrone were lower in postmenopausal patients with breast cancer, compared with benign controls. In logistic regression model, breast cancer risk increased with the decline in the levels of 4-OHE2 and 4-MeOE1. In premenopausal patients, a difference in the level of 2-OHE2 was observed between both groups, and 2-OHE2 was found to have predictive value for breast cancer. Additionally, urinary 2-OHE2 level in premenopausal hormone receptor positive (HR+) patients was considerably higher compared with hormone receptor negative patients.

          Conclusions

          We found that lower urinary levels of 4-OHE2 and 4-MeOE1 had predictive value for breast cancer, and higher 2-OHE1 were associated with HR+ breast cancer in premenopausal women.

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          Most cited references38

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          Breast cancer statistics, 2019

          This article is the American Cancer Society's biennial update on female breast cancer statistics in the United States, including data on incidence, mortality, survival, and screening. Over the most recent 5-year period (2012-2016), the breast cancer incidence rate increased slightly by 0.3% per year, largely because of rising rates of local stage and hormone receptor-positive disease. In contrast, the breast cancer death rate continues to decline, dropping 40% from 1989 to 2017 and translating to 375,900 breast cancer deaths averted. Notably, the pace of the decline has slowed from an annual decrease of 1.9% during 1998 through 2011 to 1.3% during 2011 through 2017, largely driven by the trend in white women. Consequently, the black-white disparity in breast cancer mortality has remained stable since 2011 after widening over the past 3 decades. Nevertheless, the death rate remains 40% higher in blacks (28.4 vs 20.3 deaths per 100,000) despite a lower incidence rate (126.7 vs 130.8); this disparity is magnified among black women aged <50 years, who have a death rate double that of whites. In the most recent 5-year period (2013-2017), the death rate declined in Hispanics (2.1% per year), blacks (1.5%), whites (1.0%), and Asians/Pacific Islanders (0.8%) but was stable in American Indians/Alaska Natives. However, by state, breast cancer mortality rates are no longer declining in Nebraska overall; in Colorado and Wisconsin in black women; and in Nebraska, Texas, and Virginia in white women. Breast cancer was the leading cause of cancer death in women (surpassing lung cancer) in four Southern and two Midwestern states among blacks and in Utah among whites during 2016-2017. Declines in breast cancer mortality could be accelerated by expanding access to high-quality prevention, early detection, and treatment services to all women.
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            Estrogen carcinogenesis in breast cancer.

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              17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1.

              The 4-hydroxy metabolite of 17 beta-estradiol (E2) has been implicated in the carcinogenicity of this hormone. Previous studies showed that aryl hydrocarbon-receptor agonists induced a cytochrome P450 that catalyzed the 4-hydroxylation of E2. This activity was associated with human P450 1B1. To determine the relationship of the human P450 1B1 gene product and E2 4-hydroxylation, the protein was expressed in Saccharomyces cerevisiae. Microsomes from the transformed yeast catalyzed the 4- and 2-hydroxylation of E2 with Km values of 0.71 and 0.78 microM and turnover numbers of 1.39 and 0.27 nmol product min-1.nmol P450-1, respectively. Treatment of MCF-7 human breast cancer cells with the aryl hydrocarbon-receptor ligand indolo[3,2-b]carbazole resulted in a concentration-dependent increase in P450 1B1 and P450 1A1 mRNA levels, and caused increased rates of 2-, 4-, 6 alpha-, and 15 alpha-hydroxylation of E2. At an E2 concentration of 10 nM, the increased rates of 2- and 4-hydroxylation were approximately equal, emphasizing the significance of the low Km P450 1B1-component of E2 metabolism. These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                22 November 2021
                01 December 2021
                : 10
                : 12
                : 1615-1622
                Affiliations
                [1 ]Department of Breast Surgery , West China Hospital, Sichuan University, Chengdu, China
                [2 ]Department of Breast Surgery , Cheng Du Shang Jin Nan Fu Hospital, West China Hospital, Sichuan University, Chengdu, China
                Author notes
                Correspondence should be addressed to X Yang: xiaoqinyang2019@ 123456outlook.com

                *(X Li and L Fang contributed equally to this work)

                Author information
                http://orcid.org/0000-0001-8200-3405
                Article
                EC-21-0226
                10.1530/EC-21-0226
                8679875
                34812737
                113fa324-af34-4ec8-bcd5-90ad4ab424b3
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 19 October 2021
                : 22 November 2021
                Categories
                Research

                breast cancer,liquid chromatography tandem mass spectrometry,estrogen metabolism,hormone receptor,estrogen receptor

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