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  • br Discussion br As a leading cause of death in

    2020-08-04


    4. Discussion
    As a leading cause of death in women, breast cancer remains diffi-cult to control despite advances in treatment. Although many different approaches have been used to treat breast cancer, some of these treatments display significant toxicity and may lead to drug resistance. Thus, there is an urgent need for novel drugs which target cancer Fosfomycin calcium specifically without side effects. Aside from its anti-malaria activity, ART has shown strong anti-tumor activity in previous studies, espe-cially in aggressive metastatic cancers [26]. In this study, we have demonstrated that reduced growth of breast cancer associated with ART is dependent upon the suppression of MDSCs and Tregs.
    TGF-β is involved in the function and development of mammary epithelium and promotes cancer metastasis by inducing the epithelial to mesenchymal transition (EMT) of cancer cells [27,28]. Increasing evi-dence suggests that TGF-β initially suppresses tumor growth, but that 
    constitutive activation of TGF-β promotes tumor growth [29,30]. Pre-vious clinical studies have shown that excessive TGF-β levels in breast cancer patients are associated with metastases to the bone and regional lymph nodes [31]. In this study, we have demonstrated that TGF-β protein levels in the culture supernatant of 4T1 cells and mRNA levels in the tumor decrease after ART treatment.
    MDSCs are a key immunosuppressive cell type and can suppress T cell-mediated anti-tumor immunity in breast cancer [32]. The sup-pressive abilities of MDSCs are closely related to their continuous ex-pression of ARG-1, which metabolizes l-arginine [33]. In addition, MDSCs are involved in angiogenesis, invasion, and metastasis of cancer cells [34]. Another mechanism which suppresses tumor development is the overexpression of PD1 or CTLA-4 by Tregs [35–37]. CD4+ CD25+ Foxp3+ Tregs are a type of immune cell that play an important role in controlling the balance between pro- and anti-inflammatory immune responses [38,39]. Foxp3, a transcription factor expressed in Tregs, is essential for the development and maintenance of Tregs [40]. IL-10 and TGF-β, as well as sustained expression of inhibitory CTLA-4, are key mediators of Treg-induced immunosuppression [41,42]. Suppression of anti-tumor responses by Tregs was first demonstrated in mice treated with an anti-CD25 monoclonal antibody (clone PC61), which caused regression of the tumor [43]. In the 4T1 tumor model, Treg depletion results in accumulation of CTLs in the tumor [44,45]. In the present study, ART supplementation significantly decreased the frequencies of MDSCs and Tregs in both the tumors and spleens, indicating that ART treatment can halt the immunosuppression caused by MDSCs and Tregs in 4T1 bearing mice.
    Anti-tumor immunity mediated by CTLs (CD8+ cytotoxic T cells) and CD4+ T helper 1 (Th1) cells inhibits cancer cell growth [46,47]. CD4+ Th1 cells release cytokines, including IFN-γ and TNF-α. IFN-γ stimulates the production of reactive oxygen species (ROS) and reactive
    nitrogen species (RNS) from macrophages, which leads to the destruc-tion of cancer cells [48]. Th1 cells exert their anti-tumor effects through two major mechanisms: 1) they can directly kill tumor cells by engaging the TNF-related apoptosis-inducing ligand (TRAIL) or Fas/Fas ligand (FasL) pathways [49] or 2) they can help generate and enhance CTL responses [50]. We found that ART treatment significantly increased the frequencies of CTL and Th1 cells, as well as IFN-γ and TNF-α ex-pression levels, in the tumor. In conclusion, ART inhibits breast cancer growth in vivo by promoting T cell activation as well as the suppression of Tregs and MDSCs in the tumor microenvironment.
    Acknowledgements
    These studies were supported by grants from the China Postdoctoral Science Foundation (2017M621178 to Y. Cao) and the National Natural Science Foundation of China (81773083 to Y.Y. Xu and 81773163 to F. Jin). We thank the staff in the College of Animal Science and Technology for all their assistance.
    References
    breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production,
    M. Prewett, G. Liebisch, K. Persaud, et al., Anti-transforming growth factor beta receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells, Clin. Cancer Res. 16 (4) (2010) 1191–1205.
    ARv7 Represses Tumor-Suppressor Genes in Castration-Resistant Prostate Cancer
    Graphical Abstract Authors
    Laura Cato, Jonas de Tribolet-Hardy, Irene Lee, ..., Stephen R. Plymate, Anna C. Groner, Myles Brown
    Correspondence
    [email protected] (S.R.P.), [email protected] (A.C.G.), [email protected] (M.B.)
    In Brief
    Cato et al. utilize cistrome and transcriptome analyses in castration-resistant prostate cancer (CRPC) to reveal that the androgen receptor (AR) splice variant ARv7 functions as a transcriptional repressor and heterodimerizes with full-length AR at a subset of growth-suppressive genes to support CRPC growth.