MiR-98-5p/IGF2 Axis Influence Herceptin Sensitivity through IGF1R/HER2 Heterodimer Formation and AKT/mTOR Signal Pathway in HER2 Positive Breast Cancer

BACKGROUND AND AIM: IGF1R and HER2 are both members of the growth factor receptor family which is known to play a different role in breast cancer. However, correlation between IGF1R and HER2 has created a controversial situation that need to be fully delineated in development of Herceptin resistance. The aim of this study was to investigate the mechanism of Herceptin resistance through the IGF1R pathway in HER2 positive breast cancer. MATERIALS AND METHODS: Clinical data were obtained from TCGA database and archived documents from The First Affiliated Hospital of Bengbu Medical College. Western blot and immunohistochemistry were used to detect proteins and their phosphorylation. Cell transfection were constructed using shRNA lentivirus vectors. RNAs were analyzed by RT-qPCR. Proteins in serum were analyzed by ELISA assay. Cell proliferation was analyzed by MTS method. Luciferase report experiment was conducted to verify RNA’s inter-reaction. RESULTS: Western blot showed IGF2 protein was significantly increased in Herceptin resistant SKBR3-R cells (P<0.01), and IGF1R/HER2 heterodimer level was significantly increased (P<0.01). Luciferase reporter assay verified miR-98-5p could bind to 3 ‘UTR of IGF2 mRNA. When miR-98-5p was upregulated, the expression level of IGF2 was decreased(P<0.01), the cell invasive ability was reduced(P<0.01), and ultimately, Herceptin resistant cells regained their sensitivity to Herceptin. In clinical research, we found that decreased miR-98-5p level or increased IGF2 level significantly associated with poor treatment response and poor overall survival (OS), poor recurrence free survival (RFS) and poor distant metastasis-free survival (DMFS) in HER2-positive breast cancer. Conclusion: MiR-98-5p and IGF2 might potential candidates for predicting Herceptin sensitivity and provides a new way to overcome Herceptin resistance in clinic.