NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer

Molecular Oncology
Aura KaunistoAlex Toker

Abstract

NFAT transcription factors are key regulators of gene expression in immune cells. In addition, NFAT1-induced genes play diverse roles in mediating the progression of various solid tumors. Here we show that NFAT1 induces the expression of the IL8 gene by binding to its promoter and leading to IL8 secretion. Thapsigargin stimulation of breast cancer cells induces IL8 expression in an NFAT-dependent manner. Moreover, we show that NFAT1-mediated IL8 production promotes the migration of primary human neutrophils in vitro and also promotes neutrophil infiltration in tumor xenografts. Furthermore, expression of active NFAT1 effectively suppresses the growth of nascent and established tumors by a non cell-autonomous mechanism. Evaluation of breast tumor tissue reveals that while the levels of NFAT1 are similar in tumor cells and normal breast epithelium, cells in the tumor stroma express higher levels of NFAT1 compared to normal stroma. Elevated levels of NFAT1 also correlate with increased neutrophil infiltrate in breast tumors. These data point to a mechanism by which NFAT1 orchestrates the communication between breast cancer cells and host neutrophils during breast cancer progression.

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Citations

Sep 24, 2015·Cancer Letters·Xiu-Guo HanTing-Ting Tang
Jun 6, 2019·Revista da Associação Médica Brasileira·Eduardo Carvalho de Arruda VeigaJose Maria Soares Junior
Jan 13, 2017·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·Feng ZhangHong Shi
May 29, 2018·Journal of Cancer Research and Clinical Oncology·Santhoshkumar SundaramoorthyIn Kyoung Lim
Oct 24, 2018·Frontiers in Immunology·Emile J ClappaertDamya Laoui
Apr 30, 2021·Frontiers in Immunology·Shuvasree SenGuptaCarole A Parent
Jul 11, 2021·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·Stephany Sánchez-OvandoPeter A B Wark

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