Abstract 1166: CXCR7-mediated signaling axis regulates breast cancer growth and metastasis by modulating tumor microenvironment

Abstract Chemokine CXCL12 has been shown to bind chemokine receptor CXCR4 and CXCR7. Although extensive studies have been done to elucidate the role of CXCL12/CXCR4 signalling axis in tumor growth and metastasis, not much is known about the role of CXCL12/CXCR7 signalling axis in regulating breast cancer growth and metastasis. In order to study the role of CXCR7 in breast cancer growth and metastasis, we employed two models-i) 4T1 and CXCR7 downregulated 4T1 (4T1 shRNA-CXCR7) and ii) highly metastatic 4T1.2. First we observed CXCL12 induced and CXCR7 dependent migration of breast cancer cells and CXCL12 induced activation of ERK, STAT3 and cyclin D1, a downstream target of STAT3. In orthotopic syngenic models of breast cancer, we found reduced tumor growth and metastasis of breast cancer cells genetically silenced or pharmacologically inhibited for CXCR7 or its downstream target STAT3. The downregulation or inhibition of CXCR7 or its downstream target reduced tumor proliferation, angiogenesis and macrophage (M2) recruitment to the tumor site. Further analysis revealed the role of CXCR7 in secretion of cytokines (GMCSF, M-CSF and MCP-2), and expression of MMP-9, MMP-2 and VCAM-1. Moreover, we observed that CXCR7 is highly expressed in breast cancer tissues and positively correlates with disease progression from invasive ductal carcinoma (IDC) to metastasis. These observations highlight the importance of the CXCR7 axis in regulating breast cancer growth and metastasis. Blocking the CXCL12/CXCR7/STAT3 axis and macrophage recruitment to the tumor site with CXCR7 or STAT3 inhibitor may lead to the development of novel therapeutic strategies against breast cancer. Citation Format: Nissar A. Wani. CXCR7-mediated signaling axis regulates breast cancer growth and metastasis by modulating tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1166. doi:10.1158/1538-7445.AM2014-1166