Interleukin 17A promotes cell migration, enhances anoikis resistance, and creates a microenvironment suitable for triple negative breast cancer tumor metastasis

Background The aim of this study was to investigate the role of IL-17A in the cancer microenvironment and the recurrence of triple negative breast cancer (TNBC). Methods Using human TNBC cell lines, the role of IL17-A was investigated by knocked down of IL-17A (Delta IL-17A) and by administration of IL-17A into the culture medium. Cell proliferation assays, migration assays, as well as Western blot analysis and real-time PCR, were used to evaluate IL-17A-related signaling. Three types of 4T1 cells were implanted into BALB/c mice, namely wild type (WT), Delta IL-17A, and WT + neutralizing IL-17 antibody (WT + Ab) cells. Tumor weight, necrosis area, and the number of circulating tumor cells (CTCs) were measured. Immunohistochemistry and Western blotting were used to analyze expression of CD34, CD8, and TGF-beta 1 as well as anoikis resistance. The Kaplan-Meier's method was used to correlate IL-17A expression and patient outcome, including disease-free survival (DFS) and overall survival (OS). Results Our results demonstrated that IL-17A was able to stimulate the migratory activity, but not the growth rate, of MDA-MB-231/468 cells. In vivo, for the Delta IL-17A group, there was an increase in necrosis area, a decrease in tumor CD34 expression and a reduction in the number of CTCs. Furthermore, in WT + Ab group, there was a decreased in tumor expression of CD34, fewer CD8 ( +) cells, and fewer CTCs, but an increase in expression of TGF-beta 1 expression. Both of the above were compared to the WT group. Knockdown of IL-17A also decreased anoikis resistance in human TNBC and the murine 4T1 cell lines. Kaplan-Meier analysis disclosed a negative correlation between tumor expression of IL-17A and OS in TNBC patients. Conclusion We conclude that IL-17A promotes migratory and angiogenic activity in tumors, enhances anoikis resistance, and modulates the immune landscape of the tumor microenvironment such changes favor cancer metastasis.

Automated summary

The study revealed that IL-17A promotes migratory and angiogenic activity in TNBC tumors, enhances anoikis resistance, and modulates the immune landscape of the tumor microenvironment, favoring cancer metastasis.