Abstract Interactions between chemokines and their receptors are involved in organ-specific homing and propagation of metastatic breast cancer (BrCa) cells. BrCa cells express higher levels of CXCR4 and CXCR7 mRNA and cell surface protein, than normal human mammary epithelial cells (HMECs). Recent studies show CXCR7 is highly expressed by activated endothelial cells (i.e., neovasculature), fetal liver cells, and many tumors, but not by non-transformed (or normal) human tissues. Unlike other chemokine receptors, activation of CXCR7 does not cause Ca2+ mobilization/flux or cell migration. However, CXCR7 activation by its ligands provides signals for growth, survival, and adhesion. CXCR4, CXCR7, and CXCL12 mRNAs and proteins are differentially expressed by BrCa cell lines (MCF-7 and MDA-MB-231) and breast tumor, than compared to HMEC or benign mammary tissue, respectively. Using selective G protein inhibitors, CXCR4/CXCR7-specific siRNAs as well as Amnis ImageStream, real time PCR, and active matrix metalloproteinase assays, we tested the hypothesis that CXCR7 and its interactions with CXCR4 and CXCL12 promote BrCa cell collagenase expression, alter NF-κB and ERK1/2 localization to the nucleus, and correlates with cell cycle. CXCL12-induced CXCR4 mRNA upregulation required Gβγ protein and/or JAK/STAT signal transduction; CXCL12 expression was negatively regulated by the presence of CXCR4. CXCL12-mediated CXCR7 mRNA expression in a pertussis toxin-sensitive manner. Lastly, CXCL12-dependent MMP-1 and MMP-13 mRNA expression was Gα protein-, Gβ protein-, and Gγ protein-dependent presumably through CXCR4, while elevated expression of CXCR7 suppressed these effects. Together, this study suggests that differential and cell cycle-dependent CXCR7 and CXCR4 expression plays a critical role in enhancing BrCa cell invasion and survival cell signals, which were CXCL12-dependent, but often G protein-independent. 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 1907.