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Clinicopathological and prognostic significance of Ras association and pleckstrin homology domains 1 (RAPH1) in breast cancer

  • Preclinical study
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Abstract

Background

Ras association and pleckstrin homology domains 1 (RAPH1) is involved in cytoskeleton regulation and re-epithelialisation in invasive carcinoma and, therefore, may play a key role in carcinogenesis and metastasis. We, herein, investigated the biological and clinical significance of RAPH1 in breast cancer using large annotated cohorts.

Methods

The clinicopathological and prognostic significance of RAPH1 was assessed at the genomic and transcriptomic levels using The Cancer Genome Atlas (TCGA) dataset (n = 1039) and the results were validated using the Molecular taxonomy of breast cancer international consortium (METABRIC) cohort (n = 1980). RAPH1 protein expression was evaluated by immunohistochemistry in a large, well-characterised cohort of early-stage breast cancer (n = 1040).

Results

In both the TCGA and METABRIC cohorts, RAPH1 mRNA expression and RAPH1 copy number alteration were strongly correlated. RAPH1 mRNA overexpression was significantly correlated with high expression of adhesion and EMT markers including CDH1, TGFβ1 and CD44. RAPH1 mRNA overexpression was a significant predictor of a poor prognosis (Hazard ratio 3.88; p = 0.049). High RAPH1 protein expression was associated with higher grade tumours with high proliferation index, triple negative phenotype and high E-cadherin expression. High RAPH1 protein expression was an independent predictor of shorter survival (Hazard ratio 4.37; p = 0.037).

Conclusions

High RAPH1 expression is correlated with aggressive breast cancer phenotypes and provides independent prognostic value in invasive breast cancer.

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Abbreviations

BC:

Breast cancer

BCSS:

BC-specific survival

CI:

Confidence intervals

CAN:

Copy number alteration

EMT:

Epithelial-mesenchymal transition

HR:

Hazard ratio

MET:

Mesenchymal-epithelial transition

METABRIC:

Molecular taxonomy of breast cancer international consortium

TCGA:

The cancer genome atlas

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Acknowledgements

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

Author information

Authors and Affiliations

  1. Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham, Nottingham, UK

    Sasagu Kurozumi, Chitra Joseph, Sultan Sonbul, Mohammed A. Aleskandarany, Marian Pigera, Mansour Alsaleem, Sami Alsaeed, Yousif Kariri, Christopher C. Nolan, Maria Diez-Rodriguez, Simon Johnston, Stewart G. Martin, Ian O. Ellis, Andrew R. Green & Emad A. Rakha

  2. Department of General Surgical Science, Gunma University, Graduate School of Medicine, Gunma, Japan

    Sasagu Kurozumi, Takaaki Fujii & Ken Shirabe

  3. Faculty of Medicine, Menoufyia University, Shebin al Kawm, Egypt

    Mohammed A. Aleskandarany & Emad A. Rakha

  4. Cancer Biology and Translational Research, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK

    Nigel P. Mongan

  5. Department of Pharmacology, Weill Cornell Medicine, New York, USA

    Nigel P. Mongan

  6. Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, NG5 1PB, UK

    Emad A. Rakha

Authors
  1. Sasagu Kurozumi
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  2. Chitra Joseph
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  3. Sultan Sonbul
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  4. Mohammed A. Aleskandarany
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  7. Sami Alsaeed
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  11. Simon Johnston
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  13. Takaaki Fujii
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  14. Ken Shirabe
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  15. Stewart G. Martin
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  16. Ian O. Ellis
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  18. Emad A. Rakha
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Corresponding author

Correspondence to Emad A. Rakha.

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Conflict of interest

Takaaki Fujii has received research funding from Eisai Co, Ltd. All the other authors declare that they have no conflict of interest.

Research involving human participants

This study was approved by the Nottingham Research Ethics Committee 2 (Reference title: Development of a molecular genetic classification of breast cancer). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Kurozumi, S., Joseph, C., Sonbul, S. et al. Clinicopathological and prognostic significance of Ras association and pleckstrin homology domains 1 (RAPH1) in breast cancer. Breast Cancer Res Treat 172, 61–68 (2018). https://doi.org/10.1007/s10549-018-4891-y

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  • DOI: https://doi.org/10.1007/s10549-018-4891-y

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