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Article: Overexpression of BQ323636.1 contributes to anastrozole resistance in AR+ve/ER+ve breast cancer

TitleOverexpression of BQ323636.1 contributes to anastrozole resistance in AR+ve/ER+ve breast cancer
Authors
Keywordsanastrozole
androgen receptor
AR antagonist
aromatase inhibitor resistance
BQ323636.1
breast cancer
oestrogen receptor
Issue Date9-Aug-2023
PublisherPathological Society of Great Britain and Ireland
Citation
Journal of Pathology, 2023, v. 260, n. 4, p. 156-168 How to Cite?
Abstract

Aromatase inhibitors (Ais) are used as adjuvant endocrine therapy for oestrogen receptor-positive (ER+ve) post-menopausal breast cancer patients. Ais, by inhibiting the enzyme aromatase, block the conversion of androgen to oestrogen, reducing oestrogen levels. Resistance to Ais limits their clinical utilisation. Here, we show that overexpression of BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, is associated with resistance to the non-steroidal aromatase inhibitor anastrozole in ER+ve post-menopausal breast cancer. Mechanistic study indicates that BQ overexpression enhances androgen receptor (AR) activity and in the presence of anastrozole, causes hyper-activation of AR signalling, which unexpectedly enhanced cell proliferation, through increased expression of CDK2CDK4, and CCNE1. BQ overexpression reverses the effect of anastrozole in ER+ve breast cancer in an AR-dependent manner, whilst co-treatment with the AR antagonist bicalutamide recovered its therapeutic effect both in vitro and in vivo. Thus, for BQ-overexpressing breast cancer, targeting AR can combat anastrozole resistance. Clinical study of 268 primary breast cancer samples of ER+ve patients who had been treated with non-steroidal Ais showed 32.5% (38/117) of cases with combined high nuclear expression of BQ and AR, which were found to be significantly associated with Ai resistance. Non-steroidal Ai-treated patients with high nuclear expression of both BQ and AR had poorer overall, disease-specific, and disease-free survival. These findings suggest the importance of assessing BQ and AR expression status in the primary ER+ve breast tumour prior to Ai treatment. This may save patients from inappropriate treatment and enable effective therapy to be given at an early stage. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Persistent Identifierhttp://hdl.handle.net/10722/331396
ISSN
2023 Impact Factor: 5.6
2023 SCImago Journal Rankings: 2.426
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTsoi, H-
dc.contributor.authorLok, J-
dc.contributor.authorMan, EP-
dc.contributor.authorCheng, CN-
dc.contributor.authorLeung, MH-
dc.contributor.authorYou, CP-
dc.contributor.authorChan, SY-
dc.contributor.authorChan, WL-
dc.contributor.authorKhoo, US-
dc.date.accessioned2023-09-21T06:55:20Z-
dc.date.available2023-09-21T06:55:20Z-
dc.date.issued2023-08-09-
dc.identifier.citationJournal of Pathology, 2023, v. 260, n. 4, p. 156-168-
dc.identifier.issn0022-3417-
dc.identifier.urihttp://hdl.handle.net/10722/331396-
dc.description.abstract<p>Aromatase inhibitors (Ais) are used as adjuvant endocrine therapy for oestrogen receptor-positive (ER+ve) post-menopausal breast cancer patients. Ais, by inhibiting the enzyme aromatase, block the conversion of androgen to oestrogen, reducing oestrogen levels. Resistance to Ais limits their clinical utilisation. Here, we show that overexpression of BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, is associated with resistance to the non-steroidal aromatase inhibitor anastrozole in ER+ve post-menopausal breast cancer. Mechanistic study indicates that BQ overexpression enhances androgen receptor (AR) activity and in the presence of anastrozole, causes hyper-activation of AR signalling, which unexpectedly enhanced cell proliferation, through increased expression of <em>CDK2</em>, <em>CDK4</em>, and <em>CCNE1</em>. BQ overexpression reverses the effect of anastrozole in ER+ve breast cancer in an AR-dependent manner, whilst co-treatment with the AR antagonist bicalutamide recovered its therapeutic effect both <em>in vitro</em> and <em>in vivo</em>. Thus, for BQ-overexpressing breast cancer, targeting AR can combat anastrozole resistance. Clinical study of 268 primary breast cancer samples of ER+ve patients who had been treated with non-steroidal Ais showed 32.5% (38/117) of cases with combined high nuclear expression of BQ and AR, which were found to be significantly associated with Ai resistance. Non-steroidal Ai-treated patients with high nuclear expression of both BQ and AR had poorer overall, disease-specific, and disease-free survival. These findings suggest the importance of assessing BQ and AR expression status in the primary ER+ve breast tumour prior to Ai treatment. This may save patients from inappropriate treatment and enable effective therapy to be given at an early stage. © 2023 The Authors. <em>The Journal of Pathology</em> published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>-
dc.languageeng-
dc.publisherPathological Society of Great Britain and Ireland-
dc.relation.ispartofJournal of Pathology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectanastrozole-
dc.subjectandrogen receptor-
dc.subjectAR antagonist-
dc.subjectaromatase inhibitor resistance-
dc.subjectBQ323636.1-
dc.subjectbreast cancer-
dc.subjectoestrogen receptor-
dc.titleOverexpression of BQ323636.1 contributes to anastrozole resistance in AR+ve/ER+ve breast cancer-
dc.typeArticle-
dc.identifier.doi10.1002/path.6157-
dc.identifier.scopuseid_2-s2.0-85166941471-
dc.identifier.volume260-
dc.identifier.issue4-
dc.identifier.spage156-
dc.identifier.epage168-
dc.identifier.eissn1096-9896-
dc.identifier.isiWOS:001043412400001-
dc.identifier.issnl0022-3417-

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