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A Splice Variant of NCOR2, BQ323636.1, Confers Chemoresistance in Breast Cancer by Altering the Activity of NRF2.

Published version
Peer-reviewed

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Authors

Leung, Man-Hong 
Tsoi, Ho 
Gong, Chun 
Man, Ellen Ps 
Zona, Stefania 

Abstract

Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) are vital in regulating signaling pathways that control cell survival and cell proliferation. Chemotherapeutic drugs such as anthracyclines induce cell death via ROS induction. Chemoresistance development is associated with adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. NRF2 can enhance cell growth, antioxidant expression, and chemoresistance by providing growth advantage for malignant cells. Previously, we identified BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, which can robustly predict tamoxifen resistance in primary breast cancer. In this study, we found that BQ was overexpressed in epirubicin-resistant cells and demonstrated that BQ overexpression could reduce the levels of epirubicin-induced ROS and confer epirubicin resistance. In vivo analysis using tissue microarray of primary breast cancer showed direct correlation between BQ expression and chemoresistance. In vitro experiments showed BQ could modulate NRF2 transcriptional activity and upregulate antioxidants. Luciferase reporter assays showed that although NCOR2 repressed the transcriptional activity of NRF2, the presence of BQ reduced this repressive activity. Co-immunoprecipitation confirmed that NCOR2 could bind to NRF2 and that this interaction was compromised by BQ overexpression, leading to increased transcriptional activity in NRF2. Our findings suggest BQ can regulate the NRF2 signaling pathway via interference with NCOR2 suppressive activity and reveals a novel role for BQ as a modulator of chemoresistance in breast cancer.

Description

Keywords

NCOR2, NRF2, breast cancer, chemoresistance, splice variant BQ

Journal Title

Cancers (Basel)

Conference Name

Journal ISSN

2072-6694
2072-6694

Volume Title

12

Publisher

MDPI AG
Sponsorship
Cancer Research UK (A12011)
Breast Cancer Now (2012MayPR070)
Medical Research Council (MR/N012097/1)
NIHR Imperial BRC (/)