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Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer

  • Edoardo Isnaldi
  • Domenico Ferraioli
  • Lorenzo Ferrando
  • Sylvain Brohée
  • Fabio Ferrando
  • Piero Fregatti
  • Davide Bedognetti
  • Alberto Ballestrero
  • Gabriele ZoppoliEmail author
Preclinical study
  • 124 Downloads

Abstract

Purpose

Breast cancer (BC) is a heterogeneous disorder, with variable response to systemic chemotherapy. Likewise, BC shows highly complex immune activation patterns, only in part reflecting classical histopathological subtyping. Schlafen-11 (SLFN11) is a nuclear protein we independently described as causal factor of sensitivity to DNA damaging agents (DDA) in cancer cell line models. SLFN11 has been reported as a predictive biomarker for DDA and PARP inhibitors in human neoplasms. SLFN11 has been implicated in several immune processes such as thymocyte maturation and antiviral response through the activation of interferon signaling pathway, suggesting its potential relevance as a link between immunity and cancer. In the present work, we investigated the transcriptional landscape of SLFN11, its potential prognostic value, and the clinico-pathological associations with its variability in BC.

Methods

We assessed SLFN11 determinants in a gene expression meta-set of 5061 breast cancer patients annotated with clinical data and multigene signatures.

Results

We found that 537 transcripts are highly correlated with SLFN11, identifying “immune response”, “lymphocyte activation”, and “T cell activation” as top Gene Ontology processes. We established a strong association of SLFN11 with stromal signatures of basal-like phenotype and response to chemotherapy in estrogen receptor negative (ER-) BC. We identified a distinct subgroup of patients, characterized by high SLFN11 levels, ER- status, basal-like phenotype, immune activation, and younger age. Finally, we observed an independent positive predictive role for SLFN11 in BC.

Conclusions

Our findings are suggestive of a relevant role for SLFN11 in BC and its immune and molecular variability.

Keywords

Schlafen-11 Immune signatures Basal-like phenotype Breast cancer Biomarker 

Abbreviations

BC

Breast cancer

DDA

DNA damaging agents

DFS

Disease-free survival

ER

Estrogen receptor

HT

Hormone treatment

ICR

Immunological constant of rejection

MCA

Multiple correspondence analysis

SLFN11

Schlafen-11

TNBC

Triple-negative breast cancer

Notes

Acknowledgements

GZ would like to thank Dr. P. Blandini, MD, for his invaluable scientific insights during all the phases of this project.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Availability of data and material

All raw data used for the generation of the expression set we analyzed are available in GEO under their respective publication IDs. Normalized expression data are available upon request to the Corresponding Author.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10549_2019_5313_MOESM1_ESM.docx (188 kb)
Supplementary material 1 (DOCX 187 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Edoardo Isnaldi
    • 1
  • Domenico Ferraioli
    • 1
    • 2
  • Lorenzo Ferrando
    • 1
  • Sylvain Brohée
    • 3
  • Fabio Ferrando
    • 1
    • 4
  • Piero Fregatti
    • 1
    • 4
  • Davide Bedognetti
    • 5
  • Alberto Ballestrero
    • 1
    • 4
  • Gabriele Zoppoli
    • 1
    • 4
    Email author
  1. 1.Department of Internal Medicine (DiMI)University of Genoa and Ospedale Policlinico San MartinoGenoaItaly
  2. 2.Comprehensive Cancer Center Leon BerardLyonFrance
  3. 3.Institut de Pathologie Et de Génétique a.s.b.lCharleroiBelgium
  4. 4.Ospedale Policlinico San Martino IRCCS per l’OncologiaGenoaItaly
  5. 5.Sidra Medical CenterDohaQatar

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