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CD44 induces FOXP3 expression and is related with favorable outcome in breast carcinoma

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Abstract

We studied the relationship between CD44 and Forkhead box P3 (FOXP3) gene expression in cell lines and breast carcinomas and their association with clinicopathological variables and patient outcome. We assessed messenger RNA (mRNA) expression of CD44 and FOXP3 by quantitative real-time PCR and determined the number of FOXP3+ Tregs by immunohistochemistry in 264 breast cancer specimens. CD44 was stimulated with hyaluronan treatment, and the accompanying changes in FOXP3 mRNA expression in breast cancer cell lines representing breast cancer subtype were assessed. We found that lower CD44 expression correlated with the presence of necrosis, lymph-vascular invasion, grade 3 tumors, and aggressive phenotype (HER2 and basal-like). FOXP3 mRNA correlated positively with CD44 mRNA expression and Treg content. Moreover, stimulation of CD44 expression by hyaluronan in cell lines increased FOXP3 expression, which supports that their regulation is associated. Survival analysis revealed that low CD44 expression is associated with higher frequency of recurrence. Our findings indicate that CD44 has a regulatory role in FOXP3 expression and is associated with good prognostic factors in breast cancer.

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Acknowledgements

We thank Cristina Pomares and Laura Andreu for their technical assistance and Dr. Hwai-Shi Wang for his experimental design advice.

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Authors and Affiliations

  1. Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain

    Elena Sanmartín, Fernando Ortiz-Martínez, Eloy Pomares-Navarro, Araceli García-Martínez, Montserrat Rodrigo-Baños, Marta García-Escolano & Gloria Peiró

  2. Pathology Department, Hospital de Cruces, Plaza de Cruces n° 2, ZC: 48903, Barakaldo, Spain

    Leire Andrés

  3. Pathology Department, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 87-89, ZC: 08041, Barcelona, Spain

    Enrique Lerma

  4. Pathology Department, University General Hospital of Alicante, C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain

    Francisco I. Aranda & Gloria Peiró

  5. Biotechnology Department, Immunology Division, University of Alicante, ZC: 03080, Alicante, Spain

    Pascual Martínez-Peinado & José M. Sempere-Ortells

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  1. Elena Sanmartín
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Correspondence to Elena Sanmartín.

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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. The Institutional Ethics Committees approved the protocol.

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

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by grants from the Instituto de Salud Carlos III (FIS PI10/00082), Conselleria de Sanitat-Generalitat Valenciana (AP-172/10), and Fundación de la Comunidad Valenciana para la Investigación, FCVI-HGUA (2011/PC-03; UGP-14-271).

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Elena Sanmartín and Fernando Ortiz-Martínez contributed equally to this article.

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Sanmartín, E., Ortiz-Martínez, F., Pomares-Navarro, E. et al. CD44 induces FOXP3 expression and is related with favorable outcome in breast carcinoma. Virchows Arch 470, 81–90 (2017). https://doi.org/10.1007/s00428-016-2045-3

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