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dc.contributor.authorBarkovskaya, Anna
dc.contributor.authorSeip, Kotryna
dc.contributor.authorPrasmickaite, Lina
dc.contributor.authorMills, Ian Geoffrey
dc.contributor.authorMoestue, Siver Andreas
dc.contributor.authorItkonen, Harri
dc.date.accessioned2021-02-03T13:32:48Z
dc.date.available2021-02-03T13:32:48Z
dc.date.created2020-09-24T08:36:27Z
dc.date.issued2020
dc.identifier.citationBarkovskaya, A., Seip, K., Prasmickaite, L., Mills, I. G., Moestue, S. A. & Itkonen, H. (2020). Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells. Scientific Reports, 10: 16992. doi:en_US
dc.identifier.issn2045-2322
dc.identifier.urihttps://hdl.handle.net/11250/2726016
dc.description.abstractIn this study, we probed the importance of O-GlcNAc transferase (OGT) activity for the survival of tamoxifen-sensitive (TamS) and tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERα), a transcription factor expressed in over 50% of breast cancers. ERα-positive breast cancers are successfully treated with tamoxifen; however, a significant number of patients develop tamoxifen-resistant disease. We show that in vitro development of tamoxifen-resistance is associated with increased sensitivity to the OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by increasing the expression of histone genes. This is known to mediate chromatin compaction. In contrast, TamR cells respond to OGT inhibition by activating the unfolded protein response and by significantly increasing ERRFI1 expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, which is a known driver of tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERα-positive breast cancers and breast cancers driven by ERBB2. This likely occurs via promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERα-positive tumors (p = 9.2e−8). In summary, we show that tamoxifen-resistance is associated with sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment.en_US
dc.language.isoengen_US
dc.publisherNatureen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleInhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cellsen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionpublishedVersionen_US
dc.rights.holder© 2020 The Author(s)en_US
dc.subject.nsiVDP::Medisinske Fag: 700en_US
dc.source.pagenumber10en_US
dc.source.volume10en_US
dc.source.journalScientific Reportsen_US
dc.identifier.doi10.1038/s41598-020-74083-z
dc.identifier.cristin1832809
dc.relation.projectNorges forskningsråd: 239940en_US
dc.source.articlenumber16992en_US


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