Abstract
BackgroundThe precancerous disease of breast cancer is an inevitable stage in the tumorigenesis and development of breast neoplasms. Quercetin (Que) has shown great potential in breast cancer treatment by inhibiting cell proliferation and regulating T cell function. γδ T cells are a class of nontraditional T cells that have long attracted attention due to their potential in immunotherapy. In this study, we revealed the immunomodulatory function of Que through regulation of the JAK/STAT1 signaling pathway, which was followed by the synergistic killing of breast cancer cells.MethodsIn the experimental design, we first screened target genes with or without Que treatment, and we intersected the Que target with the disease target by functional enrichment analysis. Second, MCF-10A, MCF-10AT, MCF-7 and MDA-MB-231 breast cancer cell lines were treated with Que for 0 h, 24 h and 48 h. Then, we observed the expression of its subsets by coculturing Que and γδ T cells and coculturing Que and γδ T cells with breast tumor cells to investigate their synergistic killing effect on tumor cells. Finally, Western blotting was used to reveal the changes in proteins related to the JAK/STAT1 signaling pathway after Que treatment in MCF-10AT and MCF-7 cells for 48 h.ResultsThe pathway affected by Que treatment was the JAK/STAT1 signaling pathway and was associated with precancerous breast cancer, as shown by network pharmacology analysis. Que induced apoptosis of MCF-10AT, MCF-7 and MDA-MB-231 cells in a time- and concentration-dependent manner (P < 0.05). Most importantly, Que promoted the differentiation of γδ T cells into the Vδ2 T cell subpopulation. The best ratio of effector cells to target cells (E/T) was 10:1, the killing percentages of γδ T cells against MCF-10A, MCF-10AT, MCF-7, and MDA-MB-231 were 61.44 ± 4.70, 55.52 ± 3.10, 53.94 ± 2.74, and 53.28 ± 1.73 (P = 0.114, P = 0.486, and P = 0.343, respectively), and the strongest killing effect on precancerous breast cancer cells and breast cancer cells was found when the Que concentration was 5 μM and the E/T ratio was 10:1 (64.94 ± 3.61, 64.96 ± 5.45, 55.59 ± 5.98, and 59.04 ± 5.67, respectively). In addition, our results showed that Que increased the protein levels of IFNγ-R, p-JAK2 and p-STAT1 while decreasing the protein levels of PD-L1 (P < 0.0001).ConclusionsIn conclusion, Que plays a synergistic role in killing breast cancer cells and promoting apoptosis by regulating the expression of IFNγ-R, p-JAK2, p-STAT1 and PD-L1 in the JAK/STAT1 signaling pathway and promoting the regulation of γδ T cells. Que may be a potential drug for the prevention of precancerous breast cancer and adjuvant treatment of breast cancer.
Highlights
The precancerous disease of breast cancer is an inevitable stage in the tumorigenesis and development of breast neoplasms
We investigated the effect of Que on γδ T immune cells or its inhibitory effect on breast cancer cells and explored the immunomodulatory function of Que through the JAK/Signal transducer and activator of transcription 3 (STAT1) signaling pathway and the underlying mechanisms of its synergistic killing of breast cancer cells
MCF-10AT was compared with MCF-10A, MCF-7, MDA-MB-231 cell lines at 120 μM concentration of Que, the percentage of apoptotic cell population was determined to be 79.19 ± 1.76% and 5.52 ± 0.30%, 61.95 ± 1.22%, 74.37 ± 0.80% (P = 0.004, P = 0.004, and P = 0.002, respectively) with significant statistical differences (Fig. 3E). These results indicate that Que can induce apoptosis in MCF-10AT and MCF-7, MDA-MB-231 at different periods and at different doses in a time- and concentration-dependent manner
Summary
The precancerous disease of breast cancer is an inevitable stage in the tumorigenesis and development of breast neoplasms. Quercetin (Que) has shown great potential in breast cancer treatment by inhibiting cell proliferation and regulating T cell function. Precancerous lesions of breast cancer refer to some breast diseases that are not malignant tumors but have an increased possibility of developing into malignant tumors. Selective estrogen receptor modulators and aromatase inhibitors have become regular treatments for precancerous breast cancer lesions. These two drugs target estrogen receptors, resulting in endocrine disorders and a series of side effects. Combination therapy involves targeted therapy and/or immunotherapeutic therapy combined with the traditional therapies mentioned above This new therapeutic strategy has made rapid progress in recent years with significant positive effects, providing new hope for patients with breast carcinomas
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