Sphingomyelin synthase 2 promotes the stemness of breast cancer cells via modulating NF-κB signaling pathway.

OBJECTIVES: Multi-drug resistance (MDR) to chemotherapy is the main obstacle influencing the anti-tumor effect in breast cancer, which might lead to the metastasis and recurrence of cancer. Until now, there are still no effective methods that can overcome MDR. In this study, we aimed to investigate the role of sphingomyelin synthase 2 (SMS2) in breast cancer resistance. METHODS: Quantitative RT-PCR analysis was performed to assess changes in mRNA expression. Western blot analysis was performed to detect protein expression. Inhibitory concentration value of adriamycin (ADR) was evaluated using CCK 8 assay. The stemness ability of breast cancer cells was assessed by spheroid-formation assay. Immunofluorescence staining was conducted to show the cellular distribution of proteins. Breast tumor masses were harvested from the xenograft tumor mouse model. RESULTS: SMS2 overexpression increased the IC50 values of breast cancer cells. SMS2 decreased the CD24 transcription level but increased the transcription levels of stemness-related genes including CD44, ALDH, OCT 4 and SOX2 in breast cancer cells. SMS2 overexpression promoted the nuclear translocation of phosphorylated NF-κB, while suppression of SMS2 could inhibit the NF-κB pathway. CONCLUSIONS: SMS2 increased the stemness of breast cancer cells via NF-κB signaling pathway, leading to resistance to the chemotherapeutic drug ADR. Thus, SMS2 might play a critical role in the development of breast cancer resistance, which is a previously unrecognized mechanism in breast cancer MDR development.

Application of HER2 peptide vaccines in patients with breast cancer: a systematic review and meta-analysis.

BACKGROUND: The E75 and GP2 vaccines are the few therapeutic vaccines targeting HER2 currently under clinical research for patients with breast cancer. METHODS: Databases, including the Cochrane Library, PubMed, Medline, Embase, and Web of Science, were used to retrieve clinical studies on E75 and GP2 vaccines. Retrieval time was from the beginning of database construction until May 31st, 2021. RESULTS: A total of 24 clinical studies were included in this analysis, including 1704 patients in the vaccinated group and 1248 patients in the control group. For the E75 vaccine, there were significant differences between the vaccinated group and the control group in the delayed-type hypersensitivity reaction (SMD = 0.685 95% CI 0.52-0.85, PHeterogeneity = 0.186, PDTH < 0.05) and the change in CD8+ T-cell numbers (SMD = - 0.864, 95% CI - 1.02 to - 0.709, PHeterogeneity = 0.085, PCD8+ T cell < 0.05) before and after injection. For the GP2 vaccine, there was a significant difference between the vaccinated group and the control group in the change in CD8+ T-cell numbers (SMD = - 0.584, 95% CI - 0.803 to - 0.294, PHeterogeneity = 0.397, PCD8+ T cell < 0.05) before and after injection. In addition, the clinical outcomes, including recurrence rate (RR = 0.568, 95% CI 0.444-0.727, PHeterogeneity = 0.955, PRecurrence < 0.05) and disease-free survival rate (RR = 1.149, 95% CI 1.050-1.256, PHeterogeneity = 0.003, PDFS < 0.05), of the E75-vaccinated group were different from those of the control group. However, we found that the overall survival rate with the E75 vaccine (RR = 1.032, 95% CI 0.998-1.067, PHeterogeneity = 0.476, POS > 0.05) was not different between the two groups. Local and systemic toxicity assessments of the two vaccines showed minimal side effects. CONCLUSIONS: The E75 vaccine was effective and safe in patients with breast cancer. The GP2 vaccine could elicit a strong immune response, but more trials are needed to confirm its clinical efficacy.

Bioinformatics analysis of HLA-A2 restricted neoantigen epitopes in breast cancer / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To screen candidate epitopes of breast cancer HLA-A2 restrictive neoantigen and to identify high frequency mutation sites in breast cancer neoantigen by using bioinformatics method. Methods: NCBI and GDC databases were used to search missense mutation sites formed by single nucleotide mutation in breast cancer among reported literatures and sequencing data. The new antigen epitopes were predicted by HLA-A2 antigen epitope prediction website BIMAS, SYFPEITHI and artificial neural networkbased NetMHC4.0, and the epitopes with TAP binding power less than Intermediate were eliminated. The candidate epitopes were prioritized by mutation frequency and prediction results. Results: A total of 17 high-frequency mutation genes, including BTLA, ERBB2 and NBPF12 etc, were screened by the above-mentioned methods, and a total of 26 neoantigen epitopes were identified. The binding power of epitopes predicted using BIMAS and SYFPEITHI showed great difference (P<0.05), epitopes in high priority as GSTP1 (A114V , mutation frequency of 5.94%) and BRCA2 (N991H, mutation frequency of 5.40%) etc, were expected to be candidate neo-antigen epitopes; however, their mutation frequency was relatively too low to achieve“universal use” . The possibility of these epitopes used as general breast cancer neo-antigen epitopes is less likely. Conclusion: The common mutation frequency of breast cancer is lower than that of other tumors; it ’s difficult to find“universal”new antigen epitopes of breast cancer; the individualized neoantigen vaccine may be of more promise, which needs further research.