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Combinatorial expression of microtubule-associated EB1 and ATIP3 biomarkers improves breast cancer prognosis

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Abstract

Purpose

The identification of molecular biomarkers for classification of breast cancer is needed to better stratify the patients and guide therapeutic decisions. The aim of this study was to investigate the value of MAPRE1 gene encoding microtubule-end binding proteins EB1 as a biomarker in breast cancer and evaluate whether combinatorial expression of MAPRE1 and MTUS1 gene encoding EB1-negative regulator ATIP3 may improve breast cancer diagnosis and prognosis.

Methods

Probeset intensities for MAPRE1 and MTUS1 genes were retrieved from Exonhit splice array analyses of 45 benign and 120 malignant breast tumors for diagnostic purposes. Transcriptomic analyses (U133 Affymetrix array) of one exploratory cohort of 150 invasive breast cancer patients and two independent series of 130 and 155 samples were compared with clinical data of the patients for prognostic studies. A tissue microarray from an independent cohort of 212 invasive breast tumors was immunostained with anti-EB1 and anti-ATIP3 antibodies.

Results

We show that MAPRE1 gene is a diagnostic and prognostic biomarker in breast cancer. High MAPRE1 levels correlate with tumor malignancy, high histological grade and poor clinical outcome. Combination of high-MAPRE1 and low-MTUS1 levels in tumors is significantly associated with tumor aggressiveness and reduced patient survival. IHC studies of combined EB1/ATIP3 protein expression confirmed these results.

Conclusions

These studies emphasize the importance of studying combinatorial expression of EB1 and ATIP3 genes and proteins rather than each biomarker alone. A population of highly aggressive breast tumors expressing high-EB1/low-ATIP3 may be considered for the development of new molecular therapies.

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Acknowledgements

We wish to thank Dr Céline Lefebvre for helpful discussion and Nicolas Signolle and Ibrahim Bouakka for excellent assistance. This work was supported by the INSERM, the CNRS, the University Paris-Saclay, the Institut Gustave Roussy, the A*MIDEX project (No. ANR-11-IDEX-0001-02) funded by the “Investissements d’Avenir” French Government program, managed by the ANR and ITMO Cancer AVIESAN as part of the Cancer Plan No. PC201419, the Labex LERMIT, the Fondation ARC pour la Recherche contre le Cancer, the Ligue Nationale Contre le Cancer, the association Odyssea, GEFLUC and Prolific.

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Authors and Affiliations

  1. Department of Molecular Medicine, INSERM U981, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94800, Villejuif, France

    Sylvie Rodrigues-Ferreira, Anne Nehlig, Clarisse Monchecourt, Ingrid Garberis, Véronique Scott, Fabrice André & Clara Nahmias

  2. LabEx LERMIT, University Paris Saclay, 5 Rue J-B Clément, 92296, Châtenay-Malabry, France

    Sylvie Rodrigues-Ferreira, Anne Nehlig, Clarisse Monchecourt, Ingrid Garberis, Véronique Scott, Fabrice André & Clara Nahmias

  3. University Paris Sud, 63 rue Gabriel Peri, 94270, Le Kremlin-Bicetre, France

    Sylvie Rodrigues-Ferreira, Anne Nehlig, Clarisse Monchecourt, Ingrid Garberis, Véronique Scott, Fabrice André & Clara Nahmias

  4. Inovarion, 75013, Paris, France

    Sylvie Rodrigues-Ferreira

  5. Department of Medical Oncology, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94800, Villejuif, France

    Sarah Nasr, Magali Lacroix-Triki, Suzette Delaloge & Barbara Pistilli

  6. Pathology Department, Institut Curie, PSL Research University, 26 rue d’Ulm, 75005, Paris, France

    Laetitia Fuhrmann & Anne Vincent-Salomon

  7. Department of Medical Biology and Pathology, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94805, Villejuif, France

    Philippe Vielh

  8. Translational Research Department, Breast Cancer Biology Group, Institut Curie, PSL Research University, 26 rue d’Ulm, 75005 Paris, France

    Thierry Dubois

Authors
  1. Sylvie Rodrigues-Ferreira
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  2. Anne Nehlig
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  3. Clarisse Monchecourt
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  4. Sarah Nasr
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  5. Laetitia Fuhrmann
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  9. Suzette Delaloge
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  13. Anne Vincent-Salomon
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  14. Fabrice André
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  15. Clara Nahmias
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Corresponding author

Correspondence to Clara Nahmias.

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Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

The authors declare that all experiments presented here comply with the current laws of France.

Research involving human and animal rights

This article does not contain any studies with animals performed by any of the authors. All procedures used in studies involving human participants have been previously published elsewhere and were in accordance with ethical standards of the Institut Curie and Gustave Roussy committees, and with 1964 Helsinki declaration.

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

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Rodrigues-Ferreira, S., Nehlig, A., Monchecourt, C. et al. Combinatorial expression of microtubule-associated EB1 and ATIP3 biomarkers improves breast cancer prognosis. Breast Cancer Res Treat 173, 573–583 (2019). https://doi.org/10.1007/s10549-018-5026-1

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  • DOI: https://doi.org/10.1007/s10549-018-5026-1

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