The role of EGCG, a major green tea catechin in breast cancer therapy is poorly understood. The present study tests the hypothesis that EGCG can inhibit the activation of HIF-1α and NFκB, and VEGF expression, thereby suppressing tumor angiogenesis and breast cancer progression. Sixteen eight-wk-old female mice (C57BL/6 J) were inoculated with 10^6 E0771 (mouse breast cancer) cells in the left fourth mammary gland fat pad. Eight mice received EGCG at 50–100 mg/kg/d in drinking water for 4 weeks. 8 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, heart and limb muscles were collected for measuring VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. EGCG treatment significantly reduced tumor weight over the control (0.37 ± 0.15 vs. 1.16 ± 0.30 g; P < 0.01), tumor CD (109 ± 20 vs. 156 ± 12 capillary #/mm^2; P < 0.01), tumor VEGF expression (45.72 ± 1.4 vs. 59.03 ± 3.8 pg/mg; P < 0.01), respectively. But, it has no effects on the body weight, heart weight, angiogenesis and VEGF expression in the heart and skeletal muscle of mice. EGCG at 50 μg/ml significantly inhibited the activation of HIF-1α and NFκB as well as VEGF expression in cultured E0771 cells, compared to the control, respectively. These findings support the hypothesis that EGCG, a major green tea catechin, directly targets both tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of breast cancer, which is mediated by the inhibition of HIF-1α and NFκB activation as well as VEGF expression.

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SU11248 is a selective inhibitor of certain protein kinases including VEGFR types 1-3 that are expressed in human breast cancer. The present study determines whether the anti-tumor activity of SU11248 results from the inhibition of angiogenesis, as well as direct anti-proliferation and anti-migration effects on breast tumors. Eight-wk old female mice (C57BL/6) were given SU11248 at 20-40 mg/kg/d in drinking (distilled) water for 4 wks. Control mice received drinking water only. In the 2nd wk, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored using dial calipers. At the end, tumors were isolated for measuring tumor size and intratumoral microvessel density (IMD) using CD31 immunohistochemistry. SU11248 significantly reduced tumor weight over the control (1.22 ± 0.28 vs. 3.28 ± 0.31 g; n = 8; p < 0.01) and IMD (111 ± 10 vs. 155 ± 6 IM#/mm2; p < 0.01). RT-PCR indicated that VEGFR1 and R2 were expressed in cultured E0771 cells. VEGF (10 ng/ml) caused a 42% increase in proliferation of E0771 cells, compared to the control (p < 0.01; n = 8), and there was a significant decrease in proliferation of E0771 cells treated with VEGF plus SU11248 (10 μmol/L) vs. the control (65%, p < 0.01). VEGF caused a 2-fold increase in the proliferation of HUVEC vs. the control (p < 0.01; n = 8), but its action was completely eradicated by SU11248. Neither VEGF nor SU11248 had any effect on the proliferation of cultured HAS MC. Migration assay showed that SU11248 (10 μmol/L) significantly inhibited the migration of cultured E0771 cells. SU11248 significantly inhibited the proliferation of MCF-7 and MDAMB-231 cells in a dose-related manner. These findings support the hypothesis that the antitumor activity of SU11248 on breast cancer is possibly mediated by targeting the paracrine and autocrine effects of VEGF on breast cancer to suppress tumor angiogenesis, proliferation and migration.