Abstract B38: The role of BQ323636.1, a novel splice variant of NCOR2, in modulation of oxidative stress in breast cancer

Abstract

Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) plays an important role in the signaling pathways governing survival and proliferation of breast cancer cells. Several chemotherapeutic drugs, such as taxanes, platinum compounds, and anthracyclines, induce cell death by enhancing the levels of ROS. Nuclear factor erythroid 2-related factor 2 (NRF2) is the master transcription factor regulating antioxidative responses against ROS. Overexpression of NRF2 has been found in breast cancer and it modulates oxidative stress response, leading to drug resistance in cancers. Our previous splice array study identified a novel splice variant of NCOR2, BQ323636.1 (BQ), as predictor of tamoxifen resistance in breast cancer. In the current study, we show overexpression of BQ could promote cell proliferation and protect cells from oxidative stress. In addition, overexpression of BQ could reduce the levels of ROS in breast cancer cells. We therefore hypothesized that BQ could compromise oxidative stress via the NRF2 pathway. By qPCR assay, several downstream targets of NRF2 were found to be upregulated in BQ-overexpressing cells. This suggested that NRF2 transcriptional activity could be modulated by BQ. The results from luciferase reporter assay confirmed that NCOR2 could repress the transcriptional activity via antioxidant response element (ARE), the primary binding site of NRF2 in promoter region. BQ could reverse the repressive effect of NCOR2 on ARE, suggesting that BQ might modulate NRF2 activity via NCOR2. Co-immunoprecipitation indicated NCOR2 interacted with NRF2. BQ overexpression might inhibit such an interaction. Taken together, our results suggest that BQ regulates NRF2 signaling pathway via interfering with NCOR2 activity. Our findings reveal a novel role for BQ as a modulator of NRF2 and oxidative stress in breast cancer. Citation Format: Man Hong Leung, Ho Tsoi, Ellen Pui Sum Man, Eric Wing-Fai Lam, Ui Soon Khoo. The role of BQ323636.1, a novel splice variant of NCOR2, in modulation of oxidative stress in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B38.