Clinical and biological roles of Kelch-like family member 7 in breast cancer: a marker of poor prognosis

  • Sasagu Kurozumi
  • Chitra Joseph
  • Sultan Sonbul
  • Kylie L. Gorringe
  • Marian Pigera
  • Mohammed A. Aleskandarany
  • Maria Diez-Rodriguez
  • Christopher C. Nolan
  • Takaaki Fujii
  • Ken Shirabe
  • Hiroyuki Kuwano
  • Sarah Storr
  • Stewart G. Martin
  • Ian O. Ellis
  • Andrew R. Green
  • Emad A. Rakha
Clinical trial

Abstract

Background

The functions of many proteins are tightly regulated with a complex array of cellular functions including ubiquitination. In cancer cells, aberrant ubiquitination may promote the activity of oncogenic pathways with subsequent tumour progression. Kelch-like family member 7 (KLHL7) is involved in the regulation of ubiquitination and may play a role in breast cancer (BC). Present study aims to evaluate the biological and clinical usefulness of KLHL7 in BC utilising large well-characterised cohorts with long-term follow-up.

Methods

The relationships between KLHL7 gene copy number alteration (CNA) and mRNA expression and clinicopathological variables and clinical outcomes were evaluated in 1980 patients from the METABRIC BC cohort. Prognostic significance of KLHL7 mRNA was validated using the Breast Cancer Gene-Expression Miner v4.0 datasets (n = 5206). KLHL7 protein expression was assessed using immunohistochemistry in a large annotated series of early-stage BC (n = 917) with long-term follow-up.

Results

KLHL7 CNA was significantly correlated with its mRNA expression. KLHL7 mRNA expression was higher in luminal B and basal-like molecular subtypes and in higher grade tumours. Increased KLHL7 protein expression was significantly correlated with features of aggressive phenotype including lymphovascular invasion, high histological grade, hormonal receptor negativity, high PIK3CA and p53 expression. Outcome analysis showed that high KLHL7 expression is an independent predictor of shorter survival (p = 0.0011).

Conclusions

KLHL7 appears to play an important role in BC progression. High KLHL7 protein expression identified a subgroup of BC with aggressive behaviour and provided independent prognostic information.

Keywords

Invasive breast cancer Lymphovascular invasion Prognosis Kelch-like family member 7 (KLHL7) Ubiquitination 

Notes

Acknowledgements

We thank the Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank for the provision of tissue samples. We also thank the University of Nottingham (Nottingham Life Cycle 6) for funding.

Compliance with ethical standards

Conflict of interest

FT received research funding from Eisai Co, Ltd. There were no competing interests for all other authors.

Supplementary material

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Supplementary material 1 (DOCX 17 kb)
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Supplementary material 2 (TIFF 2756 kb)
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Supplementary material 3 (TIFF 2089 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sasagu Kurozumi
    • 1
    • 2
  • Chitra Joseph
    • 1
  • Sultan Sonbul
    • 1
  • Kylie L. Gorringe
    • 3
    • 4
  • Marian Pigera
    • 1
  • Mohammed A. Aleskandarany
    • 1
    • 5
  • Maria Diez-Rodriguez
    • 1
  • Christopher C. Nolan
    • 1
  • Takaaki Fujii
    • 2
  • Ken Shirabe
    • 2
  • Hiroyuki Kuwano
    • 2
  • Sarah Storr
    • 1
  • Stewart G. Martin
    • 1
  • Ian O. Ellis
    • 1
  • Andrew R. Green
    • 1
  • Emad A. Rakha
    • 1
    • 5
  1. 1.Division of Cancer and Stem Cells, School of MedicineUniversity of NottinghamNottinghamUK
  2. 2.Department of General Surgical ScienceGunma University Graduate School of MedicineGunmaJapan
  3. 3.Cancer Genomics ProgramPeter MacCallum Cancer CentreMelbourneAustralia
  4. 4.The Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleAustralia
  5. 5.Faculty of MedicineMenoufyia UniversityShibin Al KawmEgypt

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