Abstract 5198: Different functions of the chemokine receptor CXCR3 in normal and malignant mammary epithelial cells

Abstract

Abstract Our previous studies detected chemokine receptor CXCR3 in malignant epithelium of early stage breast cancers by immunohistochemistry and the expression levels were positively correlated with significantly poorer survival. We also showed that CXCR3 contributes to metastatic potential in a murine model of metastatic breast cancer. Interestingly, although immortalized normal murine and human mammary epithelial cells (EpH4 and MCF-10A) also express CXCR3, they respond to CXCR3 ligands differently than malignant cells. Migration of tumor cells was enhanced by stimulation with CXCR3 ligands, but a negligible chemotactic response to these ligands was observed in normal cells. Signal transduction activation patterns also differ between malignant and normal cells. In tumor cells, ERK1/2 is robustly activated after CXCR3 ligand stimulation, whereas the same pathway is inhibited in normal cells. Likewise the p38 pathway is activated in tumor cells and decreased in normal cells. Thus, CXCR3 activation alters the behavior of both malignant and normal cells, but in different ways. One possible mechanism to explain different functions of CXCR3 between normal and malignant mammary epithelial cells is the expression of different CXCR3 isoforms. It has been shown that the “classical” CXCR3 receptor (CXCR3-A) mediates proliferation and migration of various cell lines, while CXCR3-B, a splice variant of CXCR3-A, has opposing functions. To determine the expression pattern of these two CXCR3 isoforms in a panel of human breast cancer cell lines, we conducted real-time quantitative PCR and showed that the CXCR3-B/CXCR3-A mRNA expression ratio is decreased (0.16-0.63) compared with normal epithelial cell line MCF-10A (2.16). CXCR3-B expression dominates in MCF-10A cells, while CXCR3-A expression dominates in tumor cells, with the most metastatic cell line (MDA-MB-231) exhibiting the lowest CXCR3-B/CXCR3-A ratio (0.16). Taken together, these data indicate that the level of CXCR3 receptor expression is not the only determinant of function; the relative amounts of CXCR3-A and CXCR3-B may also be important. Further studies will elucidate how the balance between CXCR3-A and CXCR3-B contributes to the behavior of cells and allow us to optimize therapeutic strategies targeting CXCR3. 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 5198.