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Clinicopathological significance of lipocalin 2 nuclear expression in invasive breast cancer

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Abstract

Purpose

The epithelial–mesenchymal transition (EMT) plays a key role in breast cancer progression and metastasis. Lipocalin 2 (LCN2) is involved in the regulation of EMT. The aim of this study was to investigate the clinicopathological significance of LCN2 expression in breast cancer.

Methods

The expression of LCN2 protein was immunohistochemically assessed in two well-characterised annotated cohorts of breast cancer (discovery cohort, n = 612; validation cohort, n = 1363). The relationship of LCN2 expression and subcellular location with the clinicopathological factors and outcomes of patients was analysed.

Results

Absent or reduced nuclear LCN2 expression was associated with features of aggressive behaviour, including high histological grade, high Nottingham Prognostic Index, high Ki67 labelling index, hormone receptor negativity and human epidermal growth factor receptor 2 positivity. The high cytoplasmic expression of LCN2 was correlated with lymph node positivity. The nuclear downregulation of LCN2 was correlated with the overexpression of EMT associated proteins (N-cadherin and Twist-related protein 2) and basal biomarkers (cytokeratin 5/6 and epidermal growth factor receptor). Unlike the cytoplasmic expression of LCN2, the loss of nuclear expression was a significant predictor of poor outcome. The combinatorial expression tumours with high cytoplasmic and low nuclear expression were associated with the worst prognosis.

Conclusions

Tumour cell expression of LCN2 plays a role in breast cancer progression with loss of its nuclear expression which is associated with aggressive features and poor outcome. Further functional analysis is warranted to confirm the relationship between the subcellular localisation LCN2 and behaviour of breast cancer.

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Acknowledgements

The authors thank the Breast Cancer Now Tissue Bank and the University of Nottingham and Pathological Society of Great Britain and Ireland.

Funding

This research was funded by the Pathological Society Trainees Small Grant Application (No: 2201) and the University of Nottingham (Nottingham Life Cycle 6).

Author information

Authors and Affiliations

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

    Sasagu Kurozumi, Sami Alsaeed, Nnamdi Orah, Islam M. Miligy, Chitra Joseph, Abrar Aljohani, Michael S. Toss, Andrew R. Green, Mohammed A. Aleskandarany & Emad A. Rakha

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

    Sasagu Kurozumi, Takaaki Fujii & Ken Shirabe

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

    Emad A. Rakha

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  1. Sasagu Kurozumi
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Corresponding author

Correspondence to Emad A. Rakha.

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Conflicts of interest

KS has received research grants from CHUGAI Pharmaceutical Co., Ltd. and Ono Pharmaceutical Co., Ltd. The remaining authors declare that they have no conflicts 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. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all participants in the study.

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Kurozumi, S., Alsaeed, S., Orah, N. et al. Clinicopathological significance of lipocalin 2 nuclear expression in invasive breast cancer. Breast Cancer Res Treat 179, 557–564 (2020). https://doi.org/10.1007/s10549-019-05488-2

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