Abstract: Objective　To explore the mechanism of high-intensity focused ultrasound (HIFU) enhancing the chemosensitivity of breast cancer to cisplatin (DDP) through TIR-domain-containing adaptor inducing interferon-β (TRIF)-mediated extracellular regulated protein kinase (ERK) pathway. Methods　Breast cancer cells (MDA-MB-231, MCF-7)/DDP-resistant cells were induced by intermittent action of increasing DDP concentration. The MDA-MB-231/DDP and MCF-7/DDP cells were divided into the control group, the HIFU group, the HIFU+Dimethyl sulfoxide (DMSO) group and the HIFU+fisetin group. CCK-8 was used to detect cell viability. Colony formation test was used to detect cell proliferation. Flow cytometry was used to detect cell cycle and apoptosis. Western blot assay was used to detect the expression of cell TRIF protein, drug resistance-related protein and ERK pathway protein. In vivo tumor formation test was used to detect tumor growth. Immunohistochemical method was used to detect the expression of Ki-67 in tumor tissues. Results　Compared with the parental MDA-MB-231 and MCF-7 cells, the MDA-MB-231/DDP and MCF-7/DDP cells had higher viability under the same concentration of DDP treatment, and the half inhibitory concentration (IC50) was significantly increased (P＜0.05), indicating the successful establishment of a stable anti-DPP drug-resistant cell line. Compared with the control group, the IC50, OD450 values of MDA-MB-231/DDP and MCF-7/DDP cells, number of cloned cells, percentage of S-phase cells, expression levels of B cell lymphoma-2 (Bcl-2), TRIF, p-glycoprotein (p-gp), multidrug resistance 1 (MDR1) and p-ERK1/2/ERK1/2 were significantly reduced in the HIFU group. The percentage of cells in G0/G1 phase, the apoptosis rate and the expression level of Bcl-2-associated X protein (Bax) were significantly increased (P＜0.05). Compared with the HIFU group, the IC50, OD450 values of MDA-MB-231/DDP and MCF-7/DDP cells, number of cloned cells, percentage of S-phase cells, expression levels of Bcl-2, TRIF, p-gp, MDR1 and p-ERK1/2/ERK1/2 were significantly increased in the HIFU+fisetin group, the percentage of cells in G0/G1 phase, the apoptosis rate, and the expression level of Bax were significantly reduced (P＜0.05). Compared with the control group, the tumor volume, tumor weight, the expression levels of TRIF and p-ERK1/2/ERK1/2, and the positive expression of Ki-67 were significantly reduced in the HIFU group (P＜0.05). Compared with the HIFU group, the tumor volume, tumor weight, expression levels of TRIF and p-ERK1/2/ERK1/2, and the positive expression of Ki-67 were significantly increased in the HIFU+fisetin group (P＜0.05). Conclusion　HIFU inhibits the ERK pathway mediated by TRIF expression, thereby enhancing the sensitivity of breast cancer DDP chemotherapy.

Key words: ultrasonic waves, adaptor proteins, signal transducing, breast neoplasms, cisplatin, TIR-domain-containing adaptor inducing interferon-β, extracellular regulated protein kinase, chemotherapy sensitivity