title: A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer.
abstract: Purpose:Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design:A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic datain silicoBiomarkers were immunohistochemically assessed in 697 MBCs (n= 477, training;n= 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results:Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rankP= 0.013; HR = 1.77, 1.12-2.8 andP= 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P= 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4EP= 0.016; HR = 2.38 (1.18-4.8), eIF5P= 0.022; HR = 2.55 (1.14-5.7); coexpressionP= 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions:Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required.Clin Cancer Res; 23(10); 2575-83. ©2016 AACR.
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Humphries
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Sreekumar
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authors.lastname: Sundara Rajan
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.|MRC Medical Bioinformatics Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Alastair
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authors.lastname: Droop
authors.affiliation: Department of Histopathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Charlotte A B
authors.initials: CAB
authors.lastname: Suleman
authors.affiliation: Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Carmine
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authors.lastname: Carbone
authors.affiliation: Center for Clinical Research, Västmanland County Hospital, Västerås, Sweden.|Department Medical Sciences. University of Uppsala, Uppsala, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nilsson
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hedieh
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authors.lastname: Honarpisheh
authors.affiliation: Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét, Hungary.
authors.forename: Gabor
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authors.lastname: Cserni
authors.affiliation: Calderdale Hospital, Halifax, United Kingdom.
authors.forename: Jo
authors.initials: J
authors.lastname: Dent
authors.affiliation: Surrey & Sussex NHS Trust, Redhill, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Fulford
authors.affiliation: University of Dundee/NHS Tayside, Dundee, United Kingdom.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Jordan
authors.affiliation: Barts Cancer Institute, London, United Kingdom.
authors.forename: J Louise
authors.initials: JL
authors.lastname: Jones
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Rani
authors.initials: R
authors.lastname: Kanthan
authors.affiliation: Poznan University of Medical Sciences, Greater Poland Cancer Centre, Poznan, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Litwiniuk
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Anna
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authors.lastname: Di Benedetto
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Marcella
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authors.lastname: Mottolese
authors.affiliation: Department of Histopathology, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.affiliation: Department of Histopathology, Imperial College Healthcare NHS Trust and Imperial College, Charing Cross Hospital, London, United Kingdom.
authors.forename: Sami
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authors.lastname: Shousha
authors.affiliation: University Hospital of North Staffordshire, Stoke-on Trent, United Kingdom.
authors.forename: Mark
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authors.lastname: Stephens
authors.affiliation: Cancer Studies and Molecular Medicine. University of Leicester, Leicester, United Kingdom.
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Walker
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Janina
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authors.lastname: Kulka
authors.affiliation: Faculty of Medicine & Health Sciences, Nottingham City Hospital, Nottingham, United Kingdom.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Department of Histopathology, The Pathology Centre, Queen Alexandra Hospital, Portsmouth, United Kingdom.
authors.forename: Margaret
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authors.lastname: Jeffery
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Helene H
authors.initials: HH
authors.lastname: Thygesen
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Vera
authors.initials: V
authors.lastname: Cappelletti
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Daidone
authors.affiliation: Department of Oncology and Pathology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Hedenfalk
authors.affiliation: Department Medical Sciences. University of Uppsala, Uppsala, Sweden.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Fjällskog
authors.affiliation: Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli Studi di Verona, Verona, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Melisi
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Lucy F
authors.initials: LF
authors.lastname: Stead
authors.affiliation: Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham and University of Birmingham, Birmingham, United Kingdom.
authors.forename: Abeer M
authors.initials: AM
authors.lastname: Shaaban
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. v.speirs@leeds.ac.uk.
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics*; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010448:Peptide Initiation Factors / Q000235:genetics*; D011379:Prognosis; D011804:Quinolines / Q000008:administration & dosage; D016601:RNA-Binding Proteins / Q000235:genetics*; D012727:Sex Characteristics; D059467:Transcriptome / Q000235:genetics; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D014408:Biomarkers, Tumor; D039561:Eukaryotic Initiation Factor-4E; D000068338:Everolimus; D007093:Imidazoles; D010448:Peptide Initiation Factors; D011804:Quinolines; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C531198:dactolisib