Abstract Breast cancer is a devastating clinical condition affecting more than 100,000 women in a year and is responsible for more than 40,000 deaths every year. Chemokines and their receptors have been shown to regulate various aspects of tumor development and progression. Constitutive expression of pro-inflammatory chemokines, a hallmark of many human cancers, helps establish a supportive tumor stroma, and, in some cases, directly stimulates tumor proliferation and invasion via receptors on tumor cells. Evidence suggests that CXCR2 regulate multiple functions in leukocytes, endothelial cells (ECs), and/or tumor cells and their precursors and thus play important role in tumor angiogenesis, growth and metastasis. In this study, we investigated the role of host CXCR2 expression in mammary tumor growth, neovascularization and tumor induced osteolysis using a syngenic mouse mammary tumor model. Eight week old BALB/c mice either expressing CXCR2 (mCXCR2 WT) or genomic knock down of CXCR2 (mCXCR2 −/−) were used to study the functional role of host CXCR2 in mammary tumor growth and progression. Orthotopical implantation of mammary tumors in mouse mammary fat pad reveals a significant decrease in tumor growth in mCXCR2 −/− compared to wild type mice. Knock-down of host CXCR2 has significantly reduced tumor-induced neovascularization in orthotopical tumors. Bone is the most common site of metastasis in breast cancer. To access the role of host CXCR2 in tumor-induced osteolysis and tumor growth in bone microenvironment, mammary tumor cells were implanted on calvaria. Tumor-induced osteolysis and osteoclast homing at the tumor-bone interface was significantly reduced in CXCR2 knockout mice compared to wild type mice. These results suggest that host CXCR2 may play a critical role in tumor development and angiogenesis as well as tumor-induced osteolysis. These data demonstrate direct evidence of host CXCR2 in breast cancer progression and metastasis, and will allow development of CXCR2 targeting as a novel approach to breast cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2281.