A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

Matthew P Humphries, Sreekumar Sundara Rajan, Alastair Droop, Charlotte A B Suleman, Carmine Carbone, Cecilia Nilsson, Hedieh Honarpisheh, Gabor Cserni, Jo Dent, Laura Fulford, Lee B Jordan, J Louise Jones, Rani Kanthan, Maria Litwiniuk, Anna Di Benedetto, Marcella Mottolese, Elena Provenzano, Sami Shousha, Mark Stephens, Rosemary A WalkerJanina Kulka, Ian O Ellis, Margaret Jeffery, Helene H Thygesen, Vera Cappelletti, Maria G Daidone, Ingrid A Hedenfalk, Marie-Louise Fjällskog, Davide Melisi, Lucy F Stead, Abeer M Shaaban, Valerie Speirs

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 data in silico Biomarkers 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-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 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 [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 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.

Original languageEnglish
Pages (from-to)2575-2583
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number10
Early online date16 Dec 2016
DOIs
Publication statusPublished - 15 May 2017

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor
  • Breast Neoplasms
  • Breast Neoplasms, Male
  • Disease-Free Survival
  • Eukaryotic Initiation Factor-4E
  • Everolimus
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Imidazoles
  • Male
  • Middle Aged
  • Peptide Initiation Factors
  • Prognosis
  • Quinolines
  • RNA-Binding Proteins
  • Sex Characteristics
  • Transcriptome
  • Journal Article

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