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BQ323636.1, a novel splice variant to NCOR2, as a predictor for tamoxifen resistant breast cancer

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Title: BQ323636.1, a novel splice variant to NCOR2, as a predictor for tamoxifen resistant breast cancer
Authors: Gong, C
Man, EPS
Tsoi, H
Lee, TKW
Lee, P
Ma, S-T
Wong, LS
Luk, M-Y
Rakha, EA
Green, AR
Ellis, IO
Lam, EW
Cheung, K-L
Khoo, U-S
Item Type: Journal Article
Abstract: Purpose: Adjuvant tamoxifen treatment revolutionized the management of estrogen receptor (ER)–positive breast cancers to prevent cancer recurrence; however, drug resistance compromises its clinical efficacy. The mechanisms underlying tamoxifen resistance are not fully understood, and no robust biomarker is available to reliably predict those who will be resistant. Here, we study BQ323636.1, a novel splice variant of the NCOR2 gene, and evaluate its efficacy in predicting tamoxifen resistance in patients with breast cancer. Experimental Design: A monoclonal anti-BQ323636.1 antibody that specifically recognizes the unique epitope of this splice variant was generated for in vitro mechanistic studies and for in vivo analysis by immunohistochemistry on tissue microarrays of two independent cohorts of 358 patients with more than 10 years clinical follow-up data, who had ER-positive primary breast cancer and received adjuvant tamoxifen treatment. An orthotopic mouse model was also used. Results: Overexpression of BQ323636.1 conferred resistance to tamoxifen in both in vitro and in an orthotopic mouse model. Mechanistically, coimmunoprecipitation showed BQ323636.1 could bind to NCOR2 and inhibit the formation of corepressor complex for the suppression of ER signaling. Nuclear BQ3232636.1 overexpression in patients samples was significantly associated with tamoxifen resistance (P = 1.79 × 10−6, sensitivity 52.9%, specificity 72.0%). In tamoxifen-treated patients, nuclear BQ323636.1 overexpression was significantly correlated with cancer metastasis and disease relapse. Nuclear BQ323636.1 was also significantly associated with poorer overall survival (P = 1.13 × 10−4) and disease-specific survival (P = 4.02 × 10−5). Conclusions: These findings demonstrate that BQ323636.1 can be a reliable biomarker to predict tamoxifen resistance in patients with ER-positive breast cancer.
Issue Date: 1-Aug-2018
Date of Acceptance: 4-Jan-2018
URI: http://hdl.handle.net/10044/1/55711
DOI: https://dx.doi.org/10.1158/1078-0432.CCR-17-2259
ISSN: 1078-0432
Publisher: American Association for Cancer Research
Start Page: 3681
End Page: 3691
Journal / Book Title: Clinical Cancer Research
Volume: 24
Issue: 15
Copyright Statement: ©2018 American Association for Cancer Research.
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Breast Cancer Now
Medical Research Council (MRC)
Funder's Grant Number: C37/A12011
2012NovemberPhD016
2012MayPR070
2014NovPhD326
MR/N012097/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
ESTROGEN-RECEPTOR
MESSENGER-RNA
CELLS
DOXORUBICIN
MECHANISMS
MEDICINE
BINDING
PROTEIN
GENES
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Article Number: 29420220
Online Publication Date: 2018-02-02
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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