RESUMEN
PURPOSE: Increasing evidence has shown that the transcription factor SOX4 is closely associated with the development and progression of many malignant tumors. However, the effect of SOX4 on breast cancer is unclear. In this study, we purposed to investigate the role of SOX4 in the growth and metastasis in breast cancer and the underlying mechanism. Moreover, the effect of SOX4 on cancer cell resistance to chemotherapeutic agents was also evaluated in vitro and in vivo. METHODS: We used lentivirus technique to ectopically express SOX4 in MDA-MB-231 and SUM149 cells or knockdown SOX4 in BT474 cells, and examined the effect of these changes on various cellular functions. MTT assay was used to determine the cell viability as well as resistance to chemotherapeutic agents. The regulation of SOX4 on epithelial-mesenchymal transition (EMT)-related genes was analyzed using qRT-PCR. The binding of SOX4 to the CXCR7 gene was demonstrated using chromatin immunoprecipitation assay and dual-luciferase reporter activity assay. The effect of SOX4/CXCR7 axis on metastasis was examined using Transwell migration and Matrigel invasion assays. The expression of SOX4/CXCR7 in primary tumors and metastatic foci in lymph nodes was assessed using immunohistochemistry. Cellular morphology was investigated under phase contrast microscope and transmission electron microscopy. Moreover, the effect of SOX4 on tumor growth, metastasis, and resistance to chemotherapy was also studied in vivo by using bioluminescent imaging. RESULTS: SOX4 increased breast cancer cell viability, migration, and invasion in vitro and enhanced tumor growth and metastasis in vivo. It regulated EMT-related genes and bound to CXCR7 promoter to upregulate CXCR7 transcription. Both SOX4 and CXCR7 were highly expressed in human primary tumors and metastatic foci in lymph nodes. Treatment of breast cancer cells with the CXCR7 inhibitor CCX771 reversed the SOX4 effect on cell migration and invasion. Ectopic expression of SOX4 increased the susceptibility of cells to paclitaxel. CONCLUSIONS: SOX4 plays an important role in the growth and metastasis of breast cancer. SOX4/CXCR7 may serve as potential therapeutic targets for the treatment. Paclitaxel may be a good therapeutic option if the expression level of SOX4 is high.
RESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting the programmed death (PD)-1 pathway have substantially changed the clinical management of metastatic urothelial carcinoma (mUC); however, the response rate remains low. There are ongoing efforts to identify robust biomarkers that can effectively predict the treatment response to ICIs. Previous studies have suggested that ERBB2/3 mutations are associated with the efficacy of ICIs in gallbladder carcinoma. CASE SUMMARY: We present a 59-year-old man with mUC harboring ERBB2/3 mutations (in-frame insertion of ERBB2 and ERBB3 amplification), negative PD-ligand 1 expression, and low tumor mutation burden. He received anti-PD-1 antibodies and paclitaxel as second-line treatment. After two cycles of treatment, the lung metastases had significantly shrunk, achieving good partial remission. After six cycles of combination therapy, the patient received sindilimab 200 mg once every 3 wk as maintenance monotherapy. At the last follow-up, the patient continued to exhibit a partial response and progression-free survival for as long as 19 mo. CONCLUSION: ERBB2/3 mutations may represent a predictive biomarker for selecting a subgroup of mUC patients who will benefit from ICIs.