CTLA-4 is a negative regulator of the proliferation and the effector function of T-cells. Therefore, it might be important to determine its expression on tumor cells and T-lymphocytes from cancer patients, to investigate its role in initiating and maintaining the neoplastic pathogenesis. CTLA-4 expression was detected in breast tissue by immunohistochemical staining and RT-PCR in 60 patients with breast cancer and 30 normal controls. The levels of CTLA-4 on T lymphocytes in 33 of the patients and 27 of the control group were determined by flow cytometry. Isolated peripheral blood mononuclear cells (PBMCs) were stimulated with phytohaemagglutinin (PHA). Stimulation index and IL-2 level in the cell culture supernatant were measured by MTT assay and ELISA method, respectively. Patients showed strong expression of CTLA-4 in the tumor cells of all specimens at both the protein and mRNA level, but only weakly positive or negative expression in normal breast tissue. Patients with higher mRNA level of CTLA-4 had obvious axillary lymph nodes metastases and higher clinical stage. Spontaneous expression of CD3 CTLA-4 on PBMCs of tumor patients was also significantly higher than that of the controls. Moreover, PBMCs derived from patients with high expression of CD3 CTLA-4 T-cells showed poor responsiveness to PHA stimulation and lower IL-2 production. Therefore, abnormal expression and dysregulation of CTLA-4 could partly explain the mechanism of evasion of anti-tumor immune responses in breast cancer patients and therefore highlight its importance in the development and progression of breast cancer.

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Phloretin is a flavonoid existed in various plants and has been reported to possess anticarcinogenic activity. However, the anticancer mechanism of phloretin in prostate cancer (PCa) remains unclear. Here, our in vitro and in vivo experimental data demonstrate that phloretin inhibits the phosphorylation and the activation of EGFR and then inhibits its downstream PI3K/AKT and MEK/ERK1/2 pathways in PCa cells. Inhibition of these two pathways further decreases expression of Sp1 by inhibiting Sp1 gene transcription, induces degradation of Sp1 protein by inhibiting GSK3β phosphorylation, suppresses nucleolin-enhanced translation of Sp1 mRNA by inhibiting nucleolin phosphorylation, and directly inactivates transcription activity of Sp1. Inhibition of Sp1 subsequently decreases the expression of Sp3/4, VEGF, and Survivin and then upregulates apoptosis-related proteins and downregulates cell cycle-related proteins in PCa cells. Finally, phloretin treatment in PCa cells induces cell growth inhibition and apoptosis, suggesting that phloretin may be an effective therapy compound in the treatment of prostate cancer.