NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer.
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.
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Aura
A
Kaunisto
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Whitney S
WS
Henry
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Laleh
L
Montaser-Kouhsari
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Shou-Ching
SC
Jaminet
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Eun-Yeong
EY
Oh
Department of Laboratory Medicine, Children's Hospital Boston, Boston, MA, USA.
Li
L
Zhao
Department of Laboratory Medicine, Children's Hospital Boston, Boston, MA, USA.
Hongbo R
HR
Luo
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Andrew H
AH
Beck
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Electronic address: atoker@bidmc.harvard.edu.
Alex
A
Toker
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology
C508606:CXCL8 protein, human; D016209:Interleukin-8; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D009363:Neoplasm Proteins
Breast cancer; Interleukin; Neutrophil infiltration; Nuclear factor of activated T cells 1