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

7 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

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Male Breast Neoplasms
Biomarkers
Survival
Phosphatidylinositol 3-Kinases
Computer Simulation
Research Design
Regression Analysis
Breast Neoplasms
Gene Expression
Therapeutics
Neoplasms

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

Cite this

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer. / Humphries, Matthew P; Sundara Rajan, Sreekumar; Droop, Alastair; Suleman, Charlotte A B; Carbone, Carmine; Nilsson, Cecilia; Honarpisheh, Hedieh; Cserni, Gabor; Dent, Jo; Fulford, Laura; Jordan, Lee B; Jones, J Louise; Kanthan, Rani; Litwiniuk, Maria; Di Benedetto, Anna; Mottolese, Marcella; Provenzano, Elena; Shousha, Sami; Stephens, Mark; Walker, Rosemary A; Kulka, Janina; Ellis, Ian O; Jeffery, Margaret; Thygesen, Helene H; Cappelletti, Vera; Daidone, Maria G; Hedenfalk, Ingrid A; Fjällskog, Marie-Louise; Melisi, Davide; Stead, Lucy F; Shaaban, Abeer M; Speirs, Valerie.

In: Clinical Cancer Research, Vol. 23, No. 10, 15.05.2017, p. 2575-2583.

Research output: Contribution to journalArticle

Humphries, MP, Sundara Rajan, S, Droop, A, Suleman, CAB, Carbone, C, Nilsson, C, Honarpisheh, H, Cserni, G, Dent, J, Fulford, L, Jordan, LB, Jones, JL, Kanthan, R, Litwiniuk, M, Di Benedetto, A, Mottolese, M, Provenzano, E, Shousha, S, Stephens, M, Walker, RA, Kulka, J, Ellis, IO, Jeffery, M, Thygesen, HH, Cappelletti, V, Daidone, MG, Hedenfalk, IA, Fjällskog, M-L, Melisi, D, Stead, LF, Shaaban, AM & Speirs, V 2017, 'A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer', Clinical Cancer Research, vol. 23, no. 10, pp. 2575-2583. https://doi.org/10.1158/1078-0432.CCR-16-1952
Humphries, Matthew P ; Sundara Rajan, Sreekumar ; Droop, Alastair ; Suleman, Charlotte A B ; Carbone, Carmine ; Nilsson, Cecilia ; Honarpisheh, Hedieh ; Cserni, Gabor ; Dent, Jo ; Fulford, Laura ; Jordan, Lee B ; Jones, J Louise ; Kanthan, Rani ; Litwiniuk, Maria ; Di Benedetto, Anna ; Mottolese, Marcella ; Provenzano, Elena ; Shousha, Sami ; Stephens, Mark ; Walker, Rosemary A ; Kulka, Janina ; Ellis, Ian O ; Jeffery, Margaret ; Thygesen, Helene H ; Cappelletti, Vera ; Daidone, Maria G ; Hedenfalk, Ingrid A ; Fjällskog, Marie-Louise ; Melisi, Davide ; Stead, Lucy F ; Shaaban, Abeer M ; Speirs, Valerie. / A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 10. pp. 2575-2583.
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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. {\circledC}2016 AACR.",
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",
author = "Humphries, {Matthew P} and {Sundara Rajan}, Sreekumar and Alastair Droop and Suleman, {Charlotte A B} and Carmine Carbone and Cecilia Nilsson and Hedieh Honarpisheh and Gabor Cserni and Jo Dent and Laura Fulford and Jordan, {Lee B} and Jones, {J Louise} and Rani Kanthan and Maria Litwiniuk and {Di Benedetto}, Anna and Marcella Mottolese and Elena Provenzano and Sami Shousha and Mark Stephens and Walker, {Rosemary A} and Janina Kulka and Ellis, {Ian O} and Margaret Jeffery and Thygesen, {Helene H} and Vera Cappelletti and Daidone, {Maria G} and Hedenfalk, {Ingrid A} and Marie-Louise Fj{\"a}llskog and Davide Melisi and Stead, {Lucy F} and Shaaban, {Abeer M} and Valerie Speirs",
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TY - JOUR

T1 - A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

AU - Humphries, Matthew P

AU - Sundara Rajan, Sreekumar

AU - Droop, Alastair

AU - Suleman, Charlotte A B

AU - Carbone, Carmine

AU - Nilsson, Cecilia

AU - Honarpisheh, Hedieh

AU - Cserni, Gabor

AU - Dent, Jo

AU - Fulford, Laura

AU - Jordan, Lee B

AU - Jones, J Louise

AU - Kanthan, Rani

AU - Litwiniuk, Maria

AU - Di Benedetto, Anna

AU - Mottolese, Marcella

AU - Provenzano, Elena

AU - Shousha, Sami

AU - Stephens, Mark

AU - Walker, Rosemary A

AU - Kulka, Janina

AU - Ellis, Ian O

AU - Jeffery, Margaret

AU - Thygesen, Helene H

AU - Cappelletti, Vera

AU - Daidone, Maria G

AU - Hedenfalk, Ingrid A

AU - Fjällskog, Marie-Louise

AU - Melisi, Davide

AU - Stead, Lucy F

AU - Shaaban, Abeer M

AU - Speirs, Valerie

N1 - ©2016 American Association for Cancer Research.

PY - 2017/5/15

Y1 - 2017/5/15

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Biomarkers, Tumor

KW - Breast Neoplasms

KW - Breast Neoplasms, Male

KW - Disease-Free Survival

KW - Eukaryotic Initiation Factor-4E

KW - Everolimus

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Imidazoles

KW - Male

KW - Middle Aged

KW - Peptide Initiation Factors

KW - Prognosis

KW - Quinolines

KW - RNA-Binding Proteins

KW - Sex Characteristics

KW - Transcriptome

KW - Journal Article

UR - http://eprints.whiterose.ac.uk/109588/

U2 - 10.1158/1078-0432.CCR-16-1952

DO - 10.1158/1078-0432.CCR-16-1952

M3 - Article

C2 - 27986751

VL - 23

SP - 2575

EP - 2583

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 10

ER -