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Download pose: Targeting vascular endothelial growth factor (VEGF) and estrogen receptor signaling ays concomitantly may enhance benefit in estrogen receptor–positive breast cancer. We had shown usly that the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) is a competitive tase inhibitor in vitro. Here we investigated (a) whether PTK/ZK shows both antiangiogenic and omatase inhibitory properties in vivo, and (b) whether the combination of PTK/ZK and letrozole erior to letrozole alone. erimental Design: Estrogen-dependent human breast cancer cells engineered to express aromatase 7 AROM 1 and BT474 AROM) were used. Mice were treated with vehicle, PTK/ZK (25, 50, or 100 ), letrozole, or PTK/ZK in combination with letrozole. ults: In MCF7 AROM 1 tumors, all treatments induced growth suppression and were associated reduction in cell turnover index, a composite measurement of both proliferation and apoptosis. K significantly reduced vessel density. Whereas letrozole caused tumor regression, PTK/ZK zed tumor volumes. The growth suppressive and antiangiogenic effects of PTK/ZK were confirmed 474 AROM xenografts. The addition of PTK/ZK did not enhance the growth-suppressive effects ozole. However, PTK/ZK decreased progesterone receptor (PgR) and TFF1 expression and uterine t, indicating that PTK/ZK decreases 17β-estradiol (E2) signaling in vivo. clusion: The VEGF receptor inhibitor PTK/ZK showed effects on E2-dependent gene expression tent with aromatase inhibition as well as antiangiogenesis in xenograft models of breast cancer. mbination with letrozole was not superior to letrozole alone. Overall, these results provide further The co support for a potential therapeutic approach of dual inhibition of VEGF and E2 signaling using a single agent. Clin Cancer Res; 16(16); 4178–87. ©2010 AACR.