Abstract
Saikosaponin A (SSa) is isolated from the dried root of Radix Bupleuri, an herb widely used in traditional Chinese medicine, exerting antitumor activities. The T helper cell type 1(Th1)/Th2 balance is associated with antitumor immunity in breast cancer. The present study aimed to investigate the effects of SSa on Th1/Th2 balance in breast cancer and to explore the underlying mechanisms. Breast cancer in rats was induced by intragastrical administration of 7,12-dimethyl-benz[a] anthracene once (100 mg/kg). At d91, the rats suffering from tumors were randomly divided into three groups and treated with vehicle solution (control group), tamoxifen (TAM group), and SSa (SSa group) daily for 56 days, respectively. The tumor volume reduction ratio and tumor cell proliferation were detected to assess the antitumor effect of SSa. The positive staining numbers of CD8+ and CD4+ T cells infiltrated in breast tumors were measured by immunohistochemistry to evaluate the antitumor immunity of SSa. Cytokine levels in serum secreted by Th1 cells [interferon gamma (IFN-γ), interleukin (IL)-12] and Th2 cells (IL-4, IL-10) were detected to evaluate Th1/Th2 balance. The related molecules of IL-12/signal transducers and activators of transcription 4 (STAT4) pathway were detected by immunohistochemistry staining, RT-PCR, and Western blot to explore the mechanisms of SSa. The results showed that, compared with the control group, SSa significantly inhibited tumor growth and tumor cell proliferation. SSa enhanced antitumor immunity, which was demonstrated as increased CD8+ T cells and CD4+ T cells infiltrated in tumors. SSa shifted Th1/Th2 balance toward Th1, which was confirmed as increased serum IFN-γ and IL-12 levels, while decreased serum IL-4 and IL-10 levels. SSa increased IL-12, IL-12 receptor, and phosphorylated STAT4 expressions to promote Th1 differentiation. In conclusion, the present work suggested that SSa could inhibit breast cancer growth by shifting Th1/Th2 balance toward Th1. The underlying mechanism may involve activation of the IL-12/STAT4 pathway that induced Th1 differentiation.
Highlights
Breast cancer is the most common malignant tumor with leading cancer-associated mortality among women (Chen et al, 2016; Siegel et al, 2018)
IL-12 promotes the differentiation of Th1 cells, whereas IL-4 promotes the development of Th2 cells
Signal transducer and activator of transcription 4 (STAT4) is activated upon IL-12 binding to the receptor and induces naive CD4+ T cells differentiating into Th1 cells
Summary
Breast cancer is the most common malignant tumor with leading cancer-associated mortality among women (Chen et al, 2016; Siegel et al, 2018). The host immune system plays an important role in the development and metastasis of breast cancer (Gil Del Alcazar et al, 2017). The tumor-infiltrating lymphocytes (TILs) have been recognized as a biomarker of antitumor response. Among the different TIL subsets, CD4+ or CD8+ T lymphocytes can recognize tumor antigens or eliminate tumor cells. CD4 + cells have two distinct subsets of T helper (Th) and Th2 cells with different cytokine production and underlying mechanism of action in breast cancer (Dushyanthen et al, 2015). Th1 cells produce tumor necrosis factor alpha, interferon gamma (IFN-γ), interleukin (IL)-2, and IL-12, which mediate antitumor effects. The Th2 cells produce IL-4 and IL-10 and contribute to favor tumor growth by inhibiting the host immune system. Development of new strategies that regulate Th1/Th2 balance may be beneficial for breast cancer treatment
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