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

• Published in: Molecular oncology 2015-06, Vol.9 (6), p.1140-1154
• Main Authors: Kaunisto, Aura, Henry, Whitney S., Montaser-Kouhsari, Laleh, Jaminet, Shou-Ching, Oh, Eun-Yeong, Zhao, Li, Luo, Hongbo R., Beck, Andrew H., Toker, Alex
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell adhesion & migration; Cell cycle; Cell interactions; Cell Line, Tumor; Cytokines; Epithelium; Experiments; Female; Gene expression; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Interleukin; Interleukin 8; Interleukin-8 - genetics; Interleukin-8 - metabolism; Kinases; Leukocyte migration; Leukocytes (neutrophilic); Localization; Melanoma; Metastases; Metastasis; Mice; Mice, Nude; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neutrophil Infiltration; Neutrophils; Neutrophils - metabolism; Neutrophils - pathology; NF-AT protein; NF-AT1 protein; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Nuclear factor of activated T cells 1; Proteins; Solid tumors; Stroma; Thapsigargin; Transcription factors; Tumor cells; Tumors; Xenografts
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2015.02.004

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. •NFAT1 is a transcriptional regulator of IL8 in breast cancer.•Active NFAT1 promotes IL8 production and neutrophil migration.•Active NFAT1 suppresses tumor growth in an IL8-independent mechanism.•NFAT1 levels correlate with neutrophil infiltration in breast tumor samples.