Abstract
Abstract We previously 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. The goal of the present study is to determine the cellular and molecular mechanisms underlying CXCR3-mediated breast cancer metastasis. Treatment of the human breast cancer cell line MDA-MB-231 with the CXCR3 ligand CXCL10 induced calcium mobilization and Rac activation; both responses are essential for tumor cell chemotaxis. Not surprisingly, CXCL10 enhanced migration and invasion of MDA-MB-231 cells. We also showed that CXCL10 promoted anchorage independent growth of both human malignant mammary epithelial cells (MDA-MB-231 and MDA-MB-468) and murine malignant mammary epithelial cell line 66.1 in an ERK- dependent manner. In tumor cells, ERK1/2 is robustly activated after CXCR3 ligand stimulation, whereas the same pathway is inhibited or not changed in normal cells. In addition, CXCR3 activation provided some degree of anoikis resistance to 66.1 cells. There are two isoforms of CXCR3 in human cells. 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. We determined the expression pattern of these two CXCR3 isoforms in a panel of human breast cancer cell lines by 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). Taken together, these data indicate that multiple molecular and cellular mechanisms may contribute to CXCR3-mediated breast cancer metastasis. Due to the distinct functions of CXCR3-A and CXCR3-B, the relative amounts of CXCR3-A and CXCR3-B may dictate cell behavior. Further studies will investigate how the balance between CXCR3-A and CXCR3-B regulates the metastatic potential of breast cancer cells and allow us to optimize therapeutic strategies targeting CXCR3. 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 2434. doi:10.1158/1538-7445.AM2011-2434
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