Previous data from this group demonstrate that the murine lung can metabolize estrogen. Production of 4-hydroxyestrogens (4-OHEs), putative carcinogens, is elevated within the lungs of females vs. males and accelerated by tobacco smoke exposure. The goal of this study was to assess the ability of the human lung to metabolize estrogen and determine if metabolism is altered either during lung tumorigenesis or by tobacco smoke, gender or race. Urine and lung tissue, tumor (T) and adjacent normal (N), were obtained from surgical non-small cell lung cancer (NSCLC) patients (men and women). Urine was also collected from healthy postmenopausal Caucasian and Chinese American women.

Estrogen synthesis (CYP17A1, CYP21, HSD17B3 and HSD17B7) and metabolism (CYP1B1, GSTA4, GSTT1, NQO1 and COMT) genes were expressed in 50-100% of the lung specimens (T and N), as determined by qRT-PCR. Transcripts for CYP19 and HSD3B1 were detected only in tumors, while levels of HSD17B3 (produces testosterone) were lower in tumor vs. normal tissue (P = 0.02). To determine the functional significance of the detected expression, the level of estrogen and its metabolites (EMs) were measured in human lung tissue by LC-MS2. Analyses of paired specimens (T and N) from NSCLC patients (18 women, 15 men) revealed 3 estrogens (E1, E2, E3) and 6 estrogen metabolites (2-OHE1, 2-OHE2, 4-OHE1, 4-OHE2, 2-OMeE1, 2-OMeE2). Levels of each EM were higher in tumors than in adjacent normal tissue and in tissue (T and N) from women as compared to men (P<0.05). 4-OHEs were a larger proportion of the total EMs in lung tumors (from men and women) than in matching normal lung tissue (P = 0.03), suggesting a shift towards the carcinogenic 4-hydroxylation pathway during tumorigenesis. In addition, 4-hydroxylation was increased in normal lung tissue from female current (n = 10) vs. never (n = 9) smokers (P = 0.004), with similar trends observed in urine (P = 0.04). P values were based on Wilcoxon tests.

Based on the elevated risk of lung cancer among nonsmoking Chinese American women, the urinary EM profile of healthy, never-smoking Chinese vs. Caucasian American women (age 55 - 65) matched for age and body mass index (20/group) was compared. The level of 4-OHEs (4-OHEs/total EMs) in the urine of postmenopausal Chinese women was 1.8-fold higher than that of Caucasian women (P = 0.015), suggesting estrogen metabolism may contribute to racial differences in lung cancer susceptibility. In summary, these data demonstrate that the human lung can metabolize estrogen, in particular to produce 4-OHEs. A shift towards 4-hydroxylation during lung tumorigenesis may contribute to the risk conferred by smoking, gender or race. Future studies will confirm these results in a larger population and evaluate the utility of urinary EM profiles as noninvasive biomarkers for the early detection of lung cancer. (Supported by the Estate of Jane Villon, the Kitty Jackson Fund, and Aurora and Timothy Hughes.)

Citation Format: Jing Peng, Xia Xu, William E. Smith, Sibele I. Meireles, Stacy L. Mosier, Guo Zhang, Shumenghui Zhai, Xiang Ma, Michael J. Slifker, Karthik Devarajan, Mindy S. Kurzer, Grace X. Ma, Margie L. Clapper. Estrogen metabolism within the human lung: impact of tumorigenesis, tobacco smoke, gender and race. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-090. doi:10.1158/1538-7445.AM2015-LB-090