Abstract A05: Estrogen synthesis and metabolism within the lungs of non-small cell lung cancer patients

Abstract

Abstract Although results from recent studies suggest that the female hormone estrogen promotes lung cancer development, the molecular mechanisms underlying this oncogenic activity remain to be elucidated. Previous data from this group demonstrate that estrogen is metabolized extensively within the murine lung. Exposure to tobacco smoke accelerates the production of 4-hydroxyestrogen, a putative carcinogenic estrogen metabolite that is generated primarily by CYP1B1. While these data suggest that mutagenic estrogen metabolites may contribute to lung tumorigenesis in mice, their relevance to humans remains unknown. The purpose of the present study was to determine the capacity of the human lung to synthesize and metabolize estrogen and to compare the profile of estrogen metabolites in tumor tissue from non-small cell lung cancer (NSCLC) patients with that of adjacent normal tissue. Quantitative RT-PCR analyses revealed expression of estrogen synthesis (CYP17A1, CYP21, HSD17B3 and HSD17B7) and metabolism (CYP1B1, GSTA4, GSTT1, NQO1 and COMT) genes in 50-100% of both normal lung specimens and tumors. Transcripts for the estrogen synthesis genes CYP19 and HSD3B1 were present only in tumors, while expression of GSTM1 and CYP1A1 was detected in less than 30% of both normal and tumor tissues. Expression of ERα and ERβ was comparable in both tissue types. However, tumors exhibited decreased levels of HSD17B3 (converts androstenedione to testosterone) and progesterone receptor transcripts as compared to normal tissue. In order to determine if the detected genes are functional, the estrogen metabolite profile of human lung tissue was established using liquid chromatography/tandem mass spectrometry (LC-MS2) technology. Examination of paired normal and tumor specimens from 9 female patients with NSCLC indicated the presence of 3 estrogens (E1, E2 and E3) and 6 estrogen metabolites (2-OHE1, 2-OHE2, 4-OHE1, 4-OHE2, 2-OMeE1 and 2-OMeE2). With the exception of 2-OMeEs, putative protective estrogen metabolites, the levels of all estrogen species examined were elevated 1.5-2 fold in tumor tissue as compared to adjacent normal tissue (P<0.05 by Wilcoxon signed rank test). In summary, these findings demonstrate for the first time that estrogen is metabolized within the human lung. The differential gene expression profile and altered estrogen metabolite levels in tumor versus adjacent normal tissue suggest that estrogen metabolism may play an important role in the development of human lung tumors and serve as a promising target for lung cancer prevention. Future studies will confirm these results in a larger number of patients and evaluate the potential of using gene expression signatures and estrogen metabolite profiles as biomarkers for the early detection of lung cancer. (This work was supported by the Keystone Initiative in Personalized Risk and Prevention, the Estate of Jane Villon and the Kitty Jackson Fund.) Citation Format: Jing Peng, Xia Xu, Sibele Meireles, Stacy Mosier, Michael Slifker, Karthik Devarajan, Margie Clapper. Estrogen synthesis and metabolism within the lungs of non-small cell lung cancer patients. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A05.