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dc.contributor.authorHuang, Rui
dc.contributor.authorFaratian, Dana
dc.contributor.authorSims, Andrew H
dc.contributor.authorWilson, Danielle
dc.contributor.authorThomas, Jeremy S
dc.contributor.authorHarrison, David J
dc.contributor.authorLangdon, Simon P
dc.date.accessioned2014-05-16T09:01:01Z
dc.date.available2014-05-16T09:01:01Z
dc.date.issued2014-04-11
dc.identifier.citationHuang , R , Faratian , D , Sims , A H , Wilson , D , Thomas , J S , Harrison , D J & Langdon , S P 2014 , ' Increased STAT1 signaling in endocrine-resistant breast cancer ' , PLoS One , vol. 9 , no. 4 , e94226 . https://doi.org/10.1371/journal.pone.0094226en
dc.identifier.issn1932-6203
dc.identifier.otherPURE: 118943837
dc.identifier.otherPURE UUID: 9e1dd604-0057-4fdb-9ded-ea00c734401d
dc.identifier.otherPubMed: 24728078
dc.identifier.otherScopus: 84899658186
dc.identifier.otherWOS: 000336736200048
dc.identifier.otherORCID: /0000-0001-9041-9988/work/64034329
dc.identifier.urihttp://hdl.handle.net/10023/4807
dc.descriptionFunding: China Scholarship Council, University of Edinburgh, Scottish Funding Council and Breakthrough Breast Cancer.en
dc.description.abstractProteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (MCF-7/LCC1) and fully resistant (MCF-7/LCC9) variants was performed to identify modifiers of endocrine sensitivity in breast cancer. Analysis of the expression of 120 paired phosphorylated and non-phosphorylated epitopes in key oncogenic and tumor suppressor pathways revealed that STAT1 and several phosphorylated epitopes (phospho-STAT1(Tyr701) and phospho-STAT3(Ser727)) were differentially expressed between endocrine resistant and parental controls, confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG was a more effective inhibitor of the endocrine resistant MCF-7/LCC1 and MCF-7/LCC9 lines than parental MCF-7 cells, while STAT3 inhibitors Stattic and WP1066 were equally effective in endocrine-resistant and parental lines. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Expression of STAT1 and STAT3 were measured by quantitative immunofluorescence in invasive breast cancers and matched lymph nodes. When lymph node expression was compared to its paired primary breast cancer expression, there was greater expression of cytoplasmic STAT1 (∼3.1 fold), phospho-STAT3(Ser727) (∼1.8 fold), and STAT5 (∼1.5 fold) and nuclear phospho-STAT3(Ser727) (∼1.5 fold) in the nodes. Expression levels of STAT1 and STAT3 transcript were analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532). When treatment with tamoxifen was considered, STAT1 gene expression was nearly predictive of distant metastasis-free survival (DMFS, log-rank p = 0.067), while STAT3 gene expression was predictive of DMFS (log-rank p<0.0001). Analysis of STAT1 and STAT3 protein expression in a series of 546 breast cancers also indicated that high expression of STAT3 protein was associated with improved survival (DMFS, p = 0.006). These results suggest that STAT signaling is important in endocrine resistance, and that STAT inhibitors may represent potential therapies in breast cancer, even in the resistant setting.
dc.format.extent11
dc.language.isoeng
dc.relation.ispartofPLoS Oneen
dc.rights© 2014 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subject.lccRC0254en
dc.titleIncreased STAT1 signaling in endocrine-resistant breast canceren
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0094226
dc.description.statusPeer revieweden


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