Abstract 1201: Role of the chemokine CXCL12 in the estrogen response of breast cancer cells

Abstract

Abstract The purpose of this study was to investigate the extent to which CXCL12 mediates the effects of estrogen in estrogen-responsive breast cancer cells. Expression microarray studies have identified CXCL12 as a gene regulated consistently by estrogen in estrogen-responsive breast cancer cells in our own and other laboratories and it has been reported that CXCL12 mediates the proliferative effects of estrogen. CXCL12 activates two seven transmembrane G protein-coupled receptors, CXCR4 and CXCR7, that transducer signals via heterotrimeric G-proteins. CXCR4 has long been accepted, whereas CXCR7 was identified more recently as a potential CXCL12 receptor. Methods: Expression of CXCL12, CXCR4 and CXCR7 was measured in five estrogen-responsive and five estrogen-nonresponsive breast cancer cell lines by qRT-PCR and western transfer analysis. The effects of CXCL12 on proliferation of the cells were assessed by DNA quantification and on migration in a modified Boyden chamber assay. The ability of CXCL12 to activate the downstream signalling molecules, MAPK and Akt, was measured by western transfer analysis with a phospho-specific antibodies. The motogenic responses of different breast cancer cell lines to CXCL12 were measured in modified Boyden chamber and in vitro wounding assays. The relative importance of CXCR4 in the CXCL12 response was probed with a specific inhibitor of CXCR4 receptor. Results: The expression of CXCL12, CXCR4 and CXCR7 varied greatly between the ten breast cancer cell lines analyzed. CXCL12 expression was highest in estrogen-responsive T-47D cells whereas CXCR4 and CXCR7 expression was highest in estrogen-nonresponsive MDA-MB-231 cells. CXCL12 was detected after secretion into medium conditioned by T-47D and MCF-7 breast cancer cells. CXCL12 did not stimulate the proliferation of MCF-7 or T-47D cells in the absence or presence of estrogen. CXCL12 did stimulate breast cancer cell migration in a concentration-dependent manner and cells that express high concentrations of the CXCL12 receptor were more responsive to CXCL12. CXCL12 stimulated Phosphorylation of both MAPK and Akt in estrogen-responsive and non-responsive breast cancer cells. Conclusion: This study shows that CXCL12 does not mediate the proliferative effects of estrogen on breast cancer cells. CXCL12 does however stimulate the migration of both estrogen-responsive and estrogen non-responsive breast cancer cells. CXCL12 mediates it effects in breast cancer cells by activation on both the MAPK and Akt signal transduction pathways. 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 1201. doi:10.1158/1538-7445.AM2011-1201