Abstract P6-09-11: NFATC2 suppresses the metastatic cascade in breast cancer patients

Abstract

For the patients with breast cancer, the pathological status of axillary lymph nodes is one of the most important predictor of prognosis. In recent years, the application of sentinel lymph node biopsy has provided us with an opportunity for the further study on the mechanism of lymph node metastasis in breast cancer. Through detailed pathological examination of sentinel lymph nodes, we can easily find patients who are in the early stage of lymph node metastasis - that is, the tumor cells from the primary tumor, invading the lymph nodes and successfully colonized, but not yet break through the lymph node microenvironment defense to the subsequent lymph node. It is the most important stage during lymph node metastasis. In the present study, we selected the pairing samples from breast cancer patients with early stage lymph node metastasis to carry out differential genomics research. A total of 182 genes with significant function and involved in significant signal transduction pathways were obtained. Bioinformatics method was used to screen out the mRNA, microRNA and transcription factor in the process of lymph node metastasis of breast cancer. We investigated the role of activated T cells c2 (NFATC2) in the core transcription factors as a target for further clinical and basic research. The expression of NFATC2 was detected in the tissue microarray prepared from 200 patients with primary breast cancer. After the median follow-up period of 89.5 months, it showed that the prognosis of patients with NFATC2 overexpression was significantly better than that of the control group (p = 0.022). We also measured the expression of NFATC2 in 50 pairs of breast cancer patients with lymph node metastasis. The results showed that the expression of NFATC2 in the primary tumor was significantly higher than that in the matched lymph node, suggesting that in patients with breast cancer, the down-regulate or deficiency of NFATC2 expression may be related with lymph node metastasis. We also attempted to add the expression of NFATC2 as a new parameter in the prediction model of lymph node metastasis based on preoperative clinical and pathological parameters. The area under the ROC curve obtained in the newly established model was 0.767, the expression state of NFATC2 had impact on the performance of the prediction model. Furthermore, when we removed the NFATC2 parameter, it could reduce the area under the ROC curve in the validation group, suggesting that the expression of NFATC2 in the primary tumor may be used as a predictor of the pathological state of axillary lymph nodes. In vitro and in vivo experiments, we demonstrated that NFATC2 has a significant suppression effect on the proliferation, migration and invasion of breast cancer cells. The potential NFATC2-target genes were determined by RNAseq and Chipseq. Nine differentially expressed genes were found to be regulated by NFATC2 in the Chip-seq analysis and bound to the promoter region of the gene, whereas GRAMD3 and SRGAP2 in the subsequent validation showed a positive correlation with the expression of NFATC2, suggesting that the two genes are likely to have a positive regulatory relationship with NFATC2. This study clarifies that NFATC2 may represent a therapeutic target for early metastasis breast cancer. Citation Format: Xue J, Chi Y, Chen J, Wu J. NFATC2 suppresses the metastatic cascade in breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-11.