miR-128-3p attenuates cancer-associated fibroblast and triple negative breast cancer aggressiveness by targeting TGFβ signaling pathway

Cancer-associated fibroblasts (CAFs) are one of the principal cellular populations of the tumor milieu and promote the aggressive phenotype of cancer cells via signaling pathways like TGFβ. Inhibition of key signaling pathways may suppress the malignant features of CAFs and cancer cells. Using microRNAs(miRNAs) as small endogenous regulators is one of the promising therapeutic strategies to inhibit the TGFβ signaling cascade involved in cancers such as triple negative breast cancer (TNBC). Methods: The CAF-like cells were produced in-vitro by TGFβ1 treatment and transwell co-culture with TNBC cells, MDA-MB-231. miR-128-3p was selected using computational method and miRNA database investigations. miR-128-3p transfected into the CAFs to inhibit the TGFβ signaling and its influence on cancer cells behavior and CAFs phenotype was investigated. Results: TGFβ1 treatment and transwell co-culture with cancer cells are capable methods to induce CAF phenotype and activate normal fibroblasts. miR-128-3p downregulated the expression of SMAD2, SMAD4 and TGFβRI in CAFs. Subsequently, invasion, migration, the proliferation rate, and EMT capacity of MDA-MB-231 in the vicinity of miR-128-3p transfected CAFs were attenuated. On the other hand, miR-128-3p suppressed the alpha smooth muscle actin (α-SMA) expression level in CAFs. Conclusion: The results demonstrated miR-128-3p could be a promising therapeutic target and function as an inhibitor of TGFβ signaling to suppress CAF phenotype and aggressive behaviors of TNBC cell line.