title: The prognostic significance of STAT3 in invasive breast cancer: analysis of protein and mRNA expressions in large cohorts.
abstract: Signal transducer and activator of transcription (STAT) transcription factors family are involved in diverse cellular biological functions. Reports regarding the prognostic impact of STAT3 expression in breast cancer (BC) are variable whether being a factor of poor or good prognosis. Immunohistochemical expression of phospho-STAT3 (pSTAT3) was studied in large series of invasive BC (n = 1270). pSTAT3 and STAT3 were quantified using reverse phase protein array (RPPA) on proteins extracted from macro-dissected FFPE tissues (n = 49 cases). STAT3 gene expression in the METABRIC cohort was also investigated. STAT3 gene expression prognostic impact was externally validated using the online BC gene expression data (n = 26 datasets, 4.177 patients). pSTAT3 was expressed in the nuclei and cytoplasm of invasive BC cells. Nuclear pSTAT3 overexpression was positively associated with smaller tumour size, lower grade, good NPI, negative lymphovascular invasion (LVI), ER+, PgR+, p53-, HER2-, and low Ki67LI and an improved breast cancer-specific survival (BCSS), independently of other factors. On RPPA, the mean pSTAT3 and STAT3 expressions were higher in ER+, PgR+, and smaller size tumours. Higher STAT3 transcripts in the METABRIC cohort were observed in cases with favourable prognostic criteria and as well as improved BCSS within the whole cohort, ER+ cohort with and without hormonal therapy, and ER- cohort including those who did not receive adjuvant chemotherapy. Pooled STAT3 gene expression data in the external validation cohort showed an association with improved patients' outcome (P < 0.001, HR = 0.84, 95 % CI 0.79-0.90). Results of this study suggest nuclear localisation of pSTAT3 as favourable prognostic marker in invasive BC, results re-enforced by analysis of STAT3 gene expression data. This good prognostic advantage was maintained in patients who received and who did not receive adjuvant therapy. Therefore, STAT3 could have context-dependent molecular roles of in BC, results which warrant further prospective verification in clinical trials.
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, NG5 1PB, UK. mohammed.aleskandarany@nottingham.ac.uk.|Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt. mohammed.aleskandarany@nottingham.ac.uk.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aleskandarany
authors.affiliation: School of Science & Technology, Nottingham Trent University, Nottingham, UK.
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Division of Immunology, School of Medicine, University of Nottingham, Nottingham, UK.
authors.forename: Ola H
authors.initials: OH
authors.lastname: Negm
authors.affiliation: School of Science & Technology, Nottingham Trent University, Nottingham, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.affiliation: Molecular Diagnostics and Personalised Therapeutics Unit, University of Ha'il, Ha'il, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elmouna
authors.affiliation: Molecular Diagnostics and Personalised Therapeutics Unit, University of Ha'il, Ha'il, Saudi Arabia.
authors.forename: Ibraheem
authors.initials: I
authors.lastname: Ashankyty
authors.affiliation: Molecular Diagnostics and Personalised Therapeutics Unit, University of Ha'il, Ha'il, Saudi Arabia.
authors.forename: Edem
authors.initials: E
authors.lastname: Nuglozeh
authors.affiliation: Molecular Diagnostics and Personalised Therapeutics Unit, University of Ha'il, Ha'il, Saudi Arabia.
authors.forename: Mohammad F
authors.initials: MF
authors.lastname: Fazaludeen
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, NG5 1PB, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Diez-Rodriguez
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, NG5 1PB, UK.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nolan
authors.affiliation: Division of Immunology, School of Medicine, University of Nottingham, Nottingham, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Tighe
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, NG5 1PB, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, NG5 1PB, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, NG5 1PB, UK.|Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism; D030541:Databases, Genetic; D005260:Female; D006801:Humans; D010766:Phosphorylation; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Breast cancer; METABRIC; RPPA; Reverse phase protein array; STAT3