Regulation of Cell Function and Myeloid-Derived Suppressor Cell Chemotaxis by hsa_circ_0006466-miR-1286-PDGFRA/B Axis in Triple Negative Breast Cancer.

[BACKGROUND] Circular RNAs (circRNAs) play critical regulatory roles in diverse biological processes of breast cancer. This study aimed to investigate the circRNAs potentially related to immunity in triple-negative breast cancer (TNBC).

[METHODS] We identified the dysregulated circRNAs in breast cancer using Gene Expression Omnibus (GEO) datasets. Then, their targeting microRNAs (miRNAs) were searched and overlapped with the miRNAs upstream of immune-associated genes. An immune-related circRNA-miRNA-mRNA network was constructed. Hsa_circ_0006466-miR-1286-PDGFRA/B axis was verified from perspectives of expression levels, binding relationships, cell functions, and regulation on myeloid-derived suppressor cells (MDSCs).

[RESULTS] A total of 28 circRNAs were identified to be dysregulated and related to the immune system in TNBC. The immune-related circRNA-miRNA-mRNA network consisted of 28 circRNAs, 106 miRNAs, and 205 mRNAs. Hsa_circ_0006466 and PDGFRA/B mRNA were upregulated in TNBC patients and positively correlated with MDSC levels. miR-1286 was downregulated in TNBC patients and negatively correlated with MDSC levels. Cotransfection experiments, luciferase reporter assay, and RNA pull-down analyses confirmed hsa_circ_0006466-miR-1286-PDGFRA/B axis. Hsa_circ_0006466 inhibited TNBC cell migration/invasion and proliferation via miR-1286-PDGFRA/B. MDSC differentiation from THP-1 and chemotaxis in TNBC cell medium were moderated by hsa_circ_0006466-miR-1286-PDGFRA/B axis.

[CONCLUSIONS] Our study identifies hsa_circ_0006466 as an immune-related circRNA in TNBC, functioning as a ceRNA to sponge miR-1286 and upregulate PDGFRA/B expression, thereby promoting MDSC-mediated immunosuppression and TNBC progression. Targeting this axis may offer a dual therapeutic strategy to suppress TNBC aggressiveness and reverse immune evasion.