Abstract
Abstract The Cancer Genome Atlas (TCGA) has identified alterations such as amplification, deletion, or mutation of androgen receptor (AR) in about 5% of human lung squamous cell carcinoma and adenocarcinoma. The expression of AR in human lung appears to play a crucial role in lung development and type II pneumocytes (PTII) maturation, but unlike in prostate cancer, the role of AR is not well known in non-small cell lung cancer (NSCLC). In our study, we demonstrated AR in NSCLC cell lines translocated into the nucleus over time when stimulated with synthetic androgen R1881, while addition of enzalutamide (MDV3100) or AR siRNA reduced AR nuclear localization. Using an NSCLC human tissue microarray also revealed that 10 out of 88 patients (11%) have positive AR immunohistochemical staining. Preliminary data from clonogenic assay indicated that enzalutamide might have radiosensitizing effect on certain NSCLC cells at 2 Gy, further suggesting the involvement of AR in lung cancer and its potential therapeutic value as a target. With the induction of R1881 for 30 minutes to 24 hours, certain NSCLC cells display decreased AR mRNA (0.5-0.8 fold), while others show modest increase (up to 1.5 fold), suggesting that AR regulation in these cells might be different due to their mutational landscapes. We then used predesigned 384 well panels from Bio-Rad to survey the effects of R1881, enzalutamide, and AR siRNA on mRNA expression levels of selected NSCLC cells. Distinct expression profiles were observed between cells that have wild-type and mutated KRAS. Taken together, these findings suggest that the AR signaling could be different based on KRAS mutational profiles of NSCLCs, and further work is required to reveal the underlying mechanism. Chromatin immunoprecipitation (ChIP) assay and RNA sequencing will be utilized to investigate AR interactions with androgen response elements and differential expressions in KRAS-driven NSCLC cells, respectively. Citation Format: Albert Roy Wang, Hope Beyer, Sean Brennan, Shannon Stiles, Dylan Wiese, Darya Buehler, Anwaar Saeed, Andrew M. Baschnagel, Gopal Iyer. Androgen receptor drives differential gene expression in KRAS-mediated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3946.
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