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Article

Claudin-Low Breast Cancer Inflammatory Signatures Support Polarization of M1-Like Macrophages with Protumoral Activity

1
Unidad de Investigación en Virología y Cáncer, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
2
Laboratorio de Biotecnología y Bioinformática Genómica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
3
Laboratorio Nacional de Microscopía Avanzada, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
*
Author to whom correspondence should be addressed.
Academic Editors: Georgios Giamas and Teresa Gagliano
Cancers 2021, 13(9), 2248; https://doi.org/10.3390/cancers13092248
Received: 22 March 2021 / Revised: 28 April 2021 / Accepted: 28 April 2021 / Published: 7 May 2021
(This article belongs to the Special Issue Targeting the Tumor Microenvironment)
Triple-negative breast cancer (BRCA) cells overexpress the cytokines GM-CSF, G-CSF, MCP-1, and RANTES. We have previously reported that monocytes in 3-D co-culture with BRCA cells generate M1-like macrophages with the ability to induce aggressive features in luminal BRCA cells. Here, we stimulated peripheral blood monocytes with the four cytokines, confirming their capacity to generate protumoral M1-like macrophages. We used the BRCA database to generate an M1-like macrophage gene expression signature related to these cytokines. We observed that the M1-like macrophage, Th1, and immunosuppressive signatures all coincide in claudin-low BRCA but also in mesenchymal carcinomas of colon (COAD) and bladder (BLCA), where they are associated with decreased overall survival in patients. Claudin-low is a tumor subtype with an adverse clinical outcome that remains poorly understood. This study indicates that M1 macrophages may be potential protumoral drivers in already established cancers, and may contribute to the aggressiveness and poor prognosis of claudin-low tumors. These results add to the knowledge of the claudin-low tumor microenvironment and could open a window to immunotherapy strategies to improve patient prognosis.
We previously reported that triple-negative breast cancer (BRCA) cells overexpress the cytokines GM-CSF, G-CSF, MCP-1, and RANTES, and when monocytes were 3-D co-cultured with them, M1-like macrophages were generated with the ability to induce aggressive features in luminal BRCA cell lines. These include upregulation of mesenchymal and stemness markers and invasion. In this study, we stimulated peripheral blood monocytes with the four cytokines and confirmed their capacity to generate protumoral M1-like macrophages. Using the METABRIC BRCA database, we observed that GM-CSF, MCP-1, and RANTES are associated with triple-negative BRCA and reduced overall survival, particularly in patients under 55 years of age. We propose an extended M1-like macrophage proinflammatory signature connected with these three cytokines. We found that the extended M1-like macrophage signature coexists with monocyte/macrophage, Th1 immune response, and immunosuppressive signatures, and all are enriched in claudin-low BRCA samples, and correlate with reduced patient overall survival. Furthermore, we observed that all these signatures are also present in mesenchymal carcinomas of the colon (COAD) and bladder (BLCA). The claudin-low tumor subtype has an adverse clinical outcome and remains poorly understood. This study places M1 macrophages as potential protumoral drivers in already established cancers, and as potential contributors to claudin-low aggressiveness and poor prognosis. View Full-Text
Keywords: M1-like macrophages; protumoral activity; breast cancer; claudin-low; tumor microenvironment M1-like macrophages; protumoral activity; breast cancer; claudin-low; tumor microenvironment
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MDPI and ACS Style

Suárez-Arriaga, M.C.; Méndez-Tenorio, A.; Pérez-Koldenkova, V.; Fuentes-Pananá, E.M. Claudin-Low Breast Cancer Inflammatory Signatures Support Polarization of M1-Like Macrophages with Protumoral Activity. Cancers 2021, 13, 2248. https://doi.org/10.3390/cancers13092248

AMA Style

Suárez-Arriaga MC, Méndez-Tenorio A, Pérez-Koldenkova V, Fuentes-Pananá EM. Claudin-Low Breast Cancer Inflammatory Signatures Support Polarization of M1-Like Macrophages with Protumoral Activity. Cancers. 2021; 13(9):2248. https://doi.org/10.3390/cancers13092248

Chicago/Turabian Style

Suárez-Arriaga, Mayra C., Alfonso Méndez-Tenorio, Vadim Pérez-Koldenkova, and Ezequiel M. Fuentes-Pananá 2021. "Claudin-Low Breast Cancer Inflammatory Signatures Support Polarization of M1-Like Macrophages with Protumoral Activity" Cancers 13, no. 9: 2248. https://doi.org/10.3390/cancers13092248

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