Our study reports that TRA16 is highly expressed in NSCLCs and its expression level is negatively correlated with the overall survival of NSCLC patients, and it enhances ERβ signaling pathway by direct stimulation of ERβ activity and through suppressing TR2-inhibitory effect on ERβ for cancer cell growth, suggesting TRA16 is a promising diagnostic and prognostic biomarker and potential target in NSCLC. This evidence concerns the gene ESR2 and cancer.