Estrogen metabolism in the human lung: impact of tumorigenesis, smoke, sex and race/ethnicity.

Jing Peng,William E Smith,Stacy L Riel,Xiang Ma,Michael J Slifker,Guo Zhang,Grace X Ma,Xia Xu,Sibele I Meireles,Mindy S Kurzer,Margie L Clapper,Shumenghui Zhai

doi:10.18632/oncotarget.22269

Jing Peng, William E Smith + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.22269

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Abstract

Previous data from this group demonstrate that the murine lung metabolizes estrogen. Production of the putative carcinogen 4-hydroxyestrogen (4-OHE) is elevated within the lungs of female vs. male mice and accelerated by tobacco smoke. The goal of this study was to determine if the human lung metabolizes estrogen and evaluate the impact of tumor formation, smoke, sex and race/ethnicity on metabolism. Urine and lung tissue (normal, tumor) were obtained from 49 non-small cell lung cancer patients. Healthy postmenopausal Caucasian (n = 19) and Chinese (n = 20) American women (never-smokers) donated urine. Quantitative RT-PCR analyses indicate that multiple estrogen synthesis and metabolism genes are expressed in human bronchoalveolar cells. Estrogen and its metabolites were measured in lung tissue and urine using liquid chromatography/tandem mass spectrometry. Wilcoxon rank tests were used for statistical comparisons. E1, E2, E3 and estrogen metabolites 2-OHE1, 2-OHE2, 4-OHE1, 4-OHE2, 2-OME1 and 2-OME2 were detected at higher levels in tumor vs. adjacent normal tissue and in women vs. men (P < 0.05). The proportion of 4-OHEs was higher in tumors than in normal lung tissue (P < 0.05), and elevated in normal tissue from current- vs. never-smoking women (P = 0.006); similar trends were observed in urine. The proportion of 4-OHEs in the urine of postmenopausal Chinese American women was 1.8-fold higher than that of Caucasian women (P = 0.015). These data indicate that estrogen metabolites are present in the human lung. A shift towards 4-hydroxylation during lung tumorigenesis may contribute to the risk conferred by smoking, sex or race/ethnicity.

Highlights

Smoking tobacco continues to be the primary risk factor for lung cancer development
The present study is the first to demonstrate that estrogen metabolites are present in human lung tissue
This finding extends previous reports from others indicating that E1 and E2 and transcripts/proteins encoded by estrogen synthesis genes [31,32,33] are present in human lung tissue

Summary

Introduction

Smoking tobacco continues to be the primary risk factor for lung cancer development. The etiology of lung tumors that arise in never-smokers is much less clear (~15% in men; > 50% in women worldwide) [1]. The percentage of never-smokers among women with lung cancer is much higher in Asia (60–80%) than in the US (15%) or Europe (20%) [2]. Even Chinese American women residing on the West coast of the US face a risk of lung cancer that is 4-fold higher than that of non-Hispanic. After controlling for smoking status [3]. The basis for these sex and racial/ethnic differences in lung cancer incidence remains unknown. Estrogens are hydroxylated by cytochrome P450 (CYP) 1A1 and 1B1 to form 2- and 4-hydroxylated estrogens (2-OHEs and 4-OHEs), respectively [5, 6]

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