title: Expression levels of SF3B3 correlate with prognosis and endocrine resistance in estrogen receptor-positive breast cancer.
abstract: De novo or acquired resistance to endocrine therapy limits its utility in a significant number of estrogen receptor-positive (ER-positive) breast cancers. It is crucial to identify novel targets for therapeutic intervention and improve the success of endocrine therapies. Splicing factor 3b, subunit 1 (SF3B1) mutations are described in luminal breast cancer albeit in low frequency. In this study, we evaluated the role of SF3B1 and SF3B3, critical parts of the SF3b splicing complex, in ER-positive endocrine resistance. To ascertain the role of SF3B1/SF3B3 in endocrine resistance, their expression levels were evaluated in ER-positive/endocrine-resistant cell lines (MCF-7/LCC2 and MCF-7/LCC9) using a real-time quantitative reverse transcription PCR (qRT-PCR). To further determine their clinical relevance, expression analysis was performed in a cohort of 60 paraffin-embedded ER-positive, node-negative breast carcinomas with low, intermediate, and high Oncotype DX recurrence scores. Expression levels of SF3B1 and SF3B3 and their prognostic value were validated in large cohorts using publicly available gene expression data sets including The Cancer Genome Atlas. SF3B1 and SF3B3 levels were significantly increased in ERα-positive cells with acquired tamoxifen (MCF-7/LCC2; both P<0.0002) and fulvestrant/tamoxifen resistance (MCF-7/LCC9; P=0.008 for SF3B1 and P=0.0006 for SF3B3). Expression levels of both MCF-7/LCC2 and MCF-7/LCC9 were not affected by additional treatments with E2 and/or tamoxifen. Furthermore, qRT-PCR analysis confirmed that SF3B3 expression is significantly upregulated in Oncotype DX high-risk groups when compared with low risk (P=0.019). Similarly, in publicly available breast cancer gene expression data sets, overexpression of SF3B3, but not SF3B1, was significantly correlated with overall survival. Furthermore, the correlation was significant in ER-positive, but not in ER-negative tumors.This is the first study to document the role of SF3B3 in endocrine resistance and prognosis in ER-positive breast cancer. Potential strategies for therapeutic targeting of the splicing mechanism(s) need to be evaluated.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indianapolis, IN, USA.
authors.forename: Yesim
authors.initials: Y
authors.lastname: Gökmen-Polar
authors.affiliation: Department of Biohealth Informatics, School of Informatics and Computing, IUPUI, Indianapolis, IN, USA.
authors.forename: Yaseswini
authors.initials: Y
authors.lastname: Neelamraju
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Chirayu P
authors.initials: CP
authors.lastname: Goswami
authors.affiliation: Department of Pathology and Laboratory Medicine, Indianapolis, IN, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Pathology and Laboratory Medicine, Indianapolis, IN, USA.
authors.forename: Gouthami
authors.initials: G
authors.lastname: Nallamothu
authors.affiliation: 1] Department of Biohealth Informatics, School of Informatics and Computing, IUPUI, Indianapolis, IN, USA [2] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA [3] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sarath Chandra
authors.initials: SC
authors.lastname: Janga
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Indianapolis, IN, USA [2] Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA [3] Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Badve
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000096:biosynthesis*; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C486349:SF3B3 protein, human