Molecular Determinants Of Cxcr4 Trafficking Dictate The Metastatic Potential In Breast Cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The G-protein-coupled CXC chemokine receptor 4 (CXCR4) was shown to be a major determinant in organ-specific metastasis for various cancers. The C-terminus of the receptor contains phosphorylation/ubiquitination sites and residues that interact with adaptor proteins which couple to the endocytosis machinery. Post-endocytic events that lead to a decision between degradation and recycling are hitherto poorly understood. We used fluorescently tagged receptor molecules stably expressed in breast cancer cells to establish that mutations in the protein kinase C (PKC) site of CXCR4 affect not only the cellular equilibrium between ESCRT-mediated degradation and recycling pathways but also the invasive properties. Importantly, the obtained in vitro results excellently translate to a murine model of breast cancer, in which we found that mutation of the PKC motif influences the metastatic potential. Furthermore, by using fluorescence lifetime imaging (FLIM) to measure direct protein-protein interactions via Forster resonance energy transfer (FRET) we show for the first time that ligand-dependent dimerization of CXCR4 receptors is a crucial mechanistic step in the above processes. Our findings reveal a new mechanism whereby the penetrance of a mutated receptor that exhibits resistance to its desensitization and confers an enhanced cancer migratory phenotype, is reduced through the dimerization with its wildtype counterpart. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1207. doi:10.1158/1538-7445.AM2011-1207