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

Gong, Chun and Man, Ellen P.S. and Tsoi, Ho and Lee, Terence K.W. and Paul, Lee and Mak, Sai-Ting and Wong, Lai-Shan and Luk, Mei-Yee and Rakha, Emad A. and Green, Andrew R. and Ellis, Ian O. and Lam, Eric W.F. and Cheung, Kwok-Leung and Khoo, Ui-Soon (2018) BQ323636.1, a novel splice variant to NCOR2, as a predictor for tamoxifen resistant breast cancer. Clinical Cancer Research . ISSN 1557-3265 (In Press)

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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 breast cancer patients.

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. Orthotopic mouse model was also used.

Results: Overexpression of BQ323636.1 conferred resistance to tamoxifen in both in vitro and in orthotopic mouse model. Mechanistically, co-immunoprecipitation showed BQ could bind to NCOR2 and inhibit the formation of co-repressor complex for the suppression of ER signaling. Nuclear BQ overexpression in patients samples was significantly associated with tamoxifen resistance (p= 1.79 x 10-6, sensitivity 52.9%, specificity 72.0%). In tamoxifen-treated patients, nuclear BQ overexpression was significantly correlated with cancer metastasis and disease relapse. Nuclear BQ was also significantly associated with poorer overall survival (p=1.13 x 10-4) and disease-specific survival (p=4.02 x 10-5).

Conclusions: These findings demonstrate that BQ can be a reliable biomarker to predict tamoxifen resistance in ER-positive breast cancer patients.

Item Type: Article
Additional Information: Date of acceptance is estimated.
Keywords: NCOR2/SMRT; BQ323636.1; Tamoxifen-resistance; breast cancer
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Cancer and Stem Cells
Depositing User: Eprints, Support
Date Deposited: 04 Jan 2018 11:28
Last Modified: 04 Jan 2018 13:07

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