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Article: SpliceArray profiling of breast cancer reveals a novel variant of NCOR2/SMRT that is associated with tamoxifen resistance and control of ERα transcriptional activity.

TitleSpliceArray profiling of breast cancer reveals a novel variant of NCOR2/SMRT that is associated with tamoxifen resistance and control of ERα transcriptional activity.
Authors
Issue Date2013
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2013, v. 73 n. 1, p. 246-255 How to Cite?
AbstractGene expression profiling aimed at classifying and prognosing breast cancer has yielded signatures with little, if any, concordance. However, expression arrays used in these studies do not discriminate alternate RNA splice isoforms that vary widely in cancer and may resolve this problem. In this study, we profiled splice isoforms in a panel of tamoxifen-sensitive and -resistant cell lines, defining a novel variant (BQ323636.1) of the nuclear receptor corepressor 2 (NCOR2) that was associated with tamoxifen resistance. Overexpression of this variant in a tamoxifen-sensitive cell line induced its resistance to tamoxifen. We confirmed our initial findings from cell lines in 77 breast tumors from a Chinese cohort, where BQ323636.1 expression was higher in tamoxifen-resistant patients than tamoxifen-sensitive patients. For patients who were estrogen receptor (ER)-positive and had received tamoxifen treatment, higher BQ323636.1 expression level correlated with distant metastasis. High expression level of BQ323636.1 was found to be associated with poorer overall and disease-free survival for patients who had received tamoxifen treatment. Notably, higher BQ323636.1 versus NCOR2 wild-type ratio was also associated with negative ER and progesterone receptor (PR) status, and triple-negative status (ER-/PR-/HER2- receptor status). Mechanistic investigations showed that under conditions of tamoxifen exposure, BQ323636.1 suppressed the transcriptional activity of ERalpha, exhibiting promoter-regulating functions. Our findings highlight a novel splice variant of the ERalpha corepressor NCOR2 as a candidate biomarker in breast cancer that not only predicts tamoxifen response but may be targeted to overcome tamoxifen resistance.
Persistent Identifierhttp://hdl.handle.net/10722/185786
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhang, Len_US
dc.contributor.authorGong, Cen_US
dc.contributor.authorLau, SLYen_US
dc.contributor.authorYang, Nen_US
dc.contributor.authorWong, OGWen_US
dc.contributor.authorCheung, ANYen_US
dc.contributor.authorTsang, JWHen_US
dc.contributor.authorChan, KYKen_US
dc.contributor.authorKhoo, USen_US
dc.date.accessioned2013-08-20T11:41:15Z-
dc.date.available2013-08-20T11:41:15Z-
dc.date.issued2013en_US
dc.identifier.citationCancer Research, 2013, v. 73 n. 1, p. 246-255en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttp://hdl.handle.net/10722/185786-
dc.description.abstractGene expression profiling aimed at classifying and prognosing breast cancer has yielded signatures with little, if any, concordance. However, expression arrays used in these studies do not discriminate alternate RNA splice isoforms that vary widely in cancer and may resolve this problem. In this study, we profiled splice isoforms in a panel of tamoxifen-sensitive and -resistant cell lines, defining a novel variant (BQ323636.1) of the nuclear receptor corepressor 2 (NCOR2) that was associated with tamoxifen resistance. Overexpression of this variant in a tamoxifen-sensitive cell line induced its resistance to tamoxifen. We confirmed our initial findings from cell lines in 77 breast tumors from a Chinese cohort, where BQ323636.1 expression was higher in tamoxifen-resistant patients than tamoxifen-sensitive patients. For patients who were estrogen receptor (ER)-positive and had received tamoxifen treatment, higher BQ323636.1 expression level correlated with distant metastasis. High expression level of BQ323636.1 was found to be associated with poorer overall and disease-free survival for patients who had received tamoxifen treatment. Notably, higher BQ323636.1 versus NCOR2 wild-type ratio was also associated with negative ER and progesterone receptor (PR) status, and triple-negative status (ER-/PR-/HER2- receptor status). Mechanistic investigations showed that under conditions of tamoxifen exposure, BQ323636.1 suppressed the transcriptional activity of ERalpha, exhibiting promoter-regulating functions. Our findings highlight a novel splice variant of the ERalpha corepressor NCOR2 as a candidate biomarker in breast cancer that not only predicts tamoxifen response but may be targeted to overcome tamoxifen resistance.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_US
dc.relation.ispartofCancer Researchen_US
dc.subject.meshBreast Neoplasms - geneticsen_US
dc.subject.meshDrug Resistance, Neoplasm - geneticsen_US
dc.subject.meshEstrogen Receptor alpha - biosynthesis - geneticsen_US
dc.subject.meshNuclear Receptor Co-Repressor 2 - geneticsen_US
dc.subject.meshTumor Markers, Biological - genetics - metabolismen_US
dc.titleSpliceArray profiling of breast cancer reveals a novel variant of NCOR2/SMRT that is associated with tamoxifen resistance and control of ERα transcriptional activity.en_US
dc.typeArticleen_US
dc.identifier.emailYang, N: nanyang@pathology.hku.hken_US
dc.identifier.emailWong, OGW: wonggw@hkucc.hku.hken_US
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_US
dc.identifier.emailTsang, JWH: jwhtsang@hku.hken_US
dc.identifier.emailChan, KYK: kelvinc@pathology.hku.hken_US
dc.identifier.emailKhoo, US: uskhoo@hku.hken_US
dc.identifier.authorityCheung, ANY=rp00542en_US
dc.identifier.authorityTsang, JWH=rp00278en_US
dc.identifier.authorityChan, KYK=rp00453en_US
dc.identifier.authorityKhoo, US=rp00362en_US
dc.identifier.doi10.1158/0008-5472.CAN-12-2241en_US
dc.identifier.pmid23117886en_US
dc.identifier.hkuros218463en_US
dc.identifier.volume73en_US
dc.identifier.issue1en_US
dc.identifier.spage246en_US
dc.identifier.epage255en_US
dc.identifier.isiWOS:000313019800025-
dc.publisher.placeUnited Statesen_US

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