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

// Jing Peng 1 , Sibele I. Meireles 1 , Xia Xu 2 , William E. Smith 3 , Michael J. Slifker 1 , Stacy L. Riel 1 , Shumenghui Zhai 4 , Guo Zhang 4 , Xiang Ma 4 , Mindy S. Kurzer 3 , Grace X. Ma 4 and Margie L. Clapper 1 1 Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA 2 Leidos Biomedical Research, Inc., Frederick, MD 21701, USA 3 Department of Food Science and Nutrition and Department of Medicine, University of Minnesota, St. Paul, MN 55108, USA 4 Center for Asian Health, Temple University, Philadelphia, PA 19140, USA Correspondence to: Margie L. Clapper, email: Margie.Clapper@fccc.edu Keywords: estrogen metabolism; 4-hydroxy estrogen; non-small cell lung cancer; tobacco smoke; never-smoking Chinese women Received: August 18, 2017      Accepted: September 30, 2017      Published: November 01, 2017 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. E 1 , E 2 , E 3 and estrogen metabolites 2-OHE 1 , 2-OHE 2 , 4-OHE 1 , 4-OHE 2 , 2-OME 1 and 2-OME 2 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.