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Serum miRNA-based distinct clusters define three groups of breast cancer patients with different clinicopathological and immune characteristics

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Abstract

Breast cancer (BCa) is a heterogeneous disease with different histological, prognostic and clinical aspects. Therefore, the need for identification of novel biomarkers for diagnosis, prognosis and monitoring of disease, as well as treatment outcome prediction remains at the forefront of research. The search for circulating elements, obtainable by simple peripheral blood withdrawal, which may serve as possible biomarkers, constitutes still a challenge. In the present study, we have evaluated the expression of 6 circulating miRNAs, (miR-16, miR-21, miR-23α, miR-146α, miR-155 and miR-181α), in operable BCa patients, with non-metastatic, invasive ductal carcinoma, not receiving neoadjuvant chemotherapy. These miRNAs, known to be involved in both tumor cell progression and immune pathways regulation, were analyzed in relation to circulating cytokines, tumor immune-cell infiltration and established prognostic clinicopathological characteristics. We have identified three different clusters, with overall low (C1), moderate (C2) or high (C3) expression levels of these six circulating miRNAs, which define three distinct groups of non-metastatic BCa patients characterized by different clinicopathological and immune-related characteristics, with possibly different clinical outcomes. Our data provide the proof-of-principle to support the notion that, up- or down-regulation of the same circulating miRNA may reflect different prognosis in BCa. Nonetheless, the prognostic and/or predictive potential of these three “signatures” needs to be further evaluated in larger cohorts of BCa patients with an, at least, 5-year clinical follow-up.

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Abbreviations

AJCC:

American Joint Committee on Cancer

BCa:

Breast cancer

DAB:

Diaminobenzidine

ER:

Estrogen receptor

FCIS:

Favorable combined immune signatures

FFPE:

Formalin-fixed, paraffin-embedded

HE:

Hematoxylin Eosin

HER2:

Human epidermal growth factor receptor 2

HLA:

Human leukocyte antigen

IL:

Interleukin

IL-1Rα:

Interleukin 1 receptor antagonist

IM:

Invasive margin

LncRNA:

Long noncoding RNA

MHC:

Major histocompatibility complex

miRNA:

MicroRNA

mRNA:

Messenger RNA

NF-kB:

Nuclear factor kappa beta

PR:

Progesterone receptor

ROC:

Receiver operating characteristic

T:

Tumor size

TC:

Tumor center

TGF-β:

Transforming growth factor beta

Treg:

T regulatory (cell)

UCIS:

Unfavorable combined immune signatures

UTR:

Untranslated region

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Funding

This study was supported by grant GER_1968 (acronym ISPEBREAST) to Constantin Baxevanis from a bilateral research and innovation cooperation, funded by the General Secretariat for Research and Technology (GSRT) of the Ministry of Education, Research and Religious Affairs of the Hellenic Republic and the German Federal Ministry for Education and Research (BMBF), and a donation to Sonia Perez from the Haegeman-Goossens family, Netherlands.

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Authors and Affiliations

  1. Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras avenue, 11522, Athens, Greece

    Sotirios P. Fortis, Christoforos K. Vaxevanis, Louisa G. Mahaira, Constantin N. Baxevanis & Sonia A. Perez

  2. Pathology Department, Saint Savas Cancer Hospital, Athens, Greece

    Michael Sofopoulos, Nectaria N. Sotiriadou & Niki Arnogiannaki

  3. Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens, Greece

    Amalia Dinou & Catherine Stavropoulos-Giokas

  4. Biomedical Research Foundation, Academy of Athens, Athens, Greece

    Dimitris Thanos

Authors
  1. Sotirios P. Fortis
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  2. Christoforos K. Vaxevanis
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  3. Louisa G. Mahaira
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  4. Michael Sofopoulos
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  6. Amalia Dinou
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  7. Niki Arnogiannaki
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  8. Catherine Stavropoulos-Giokas
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  9. Dimitris Thanos
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  10. Constantin N. Baxevanis
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  11. Sonia A. Perez
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Contributions

Sotirios P. Fortis designed and performed research, analyzed data, and wrote the manuscript; Christoforos K. Vaxevanis performed research, analyzed data and wrote the manuscript; Louisa G. Mahaira, Michael Sofopoulos, Nectaria N. Sotiriadou, Amalia Dinou, Niki Arnogiannaki, Catherine Stavropoulos-Giokas, contributed to experimental design, and performed research; Dimitris Thanos contributed to experimental design and data analysis; Constantin N. Baxevanis contributed to experimental design, data analysis, and wrote the manuscript; Sonia A. Perez supervised the study, contributed to experimental design, data analysis, and wrote the manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Sonia A. Perez.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Institutional Review Board of St. Savas Cancer Hospital (IRB-ID 6079/448/10-6-13).

Ethical standards

All prospectively enrolled patients signed a written informed consent, approved by the Review Board at St. Savas Cancer Hospital. All data of other retrospectively analyzed patients were obtained from an anonymized database constructed for the purposes of a previous study [24]. Healthy volunteers presented as blood donors at the Blood Collection and Transfusion Department of Saint Savas Hospital. They fulfilled all requirements for blood donation. Volunteers consented verbally, and no personal information was recorded. All procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Fortis, S.P., Vaxevanis, C.K., Mahaira, L.G. et al. Serum miRNA-based distinct clusters define three groups of breast cancer patients with different clinicopathological and immune characteristics. Cancer Immunol Immunother 68, 57–70 (2019). https://doi.org/10.1007/s00262-018-2252-7

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