CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival

The cytokine C-X-C motif chemokine 12 (CXCL12) is synthesised by metastasis target tissues and has been shown to attract tumour cells that express the receptor, C-X-C chemokine receptor type 4 (CXCR4). However, epigenetic silencing of CXCL12 has recently been reported to increase the metastatic potential of breast cancer cells and the reintroduction of the cytokine gene into MDA-MB-231 breast carcinoma cells decreases the number of metastases formed in vivo. We therefore wished to know whether CXCL12 expression correlates with relapse-free and overall survival in human breast cancer patients. The expression of C-X-C motif chemokine 12 (CXCL12) and C-X-C chemokine receptor type 4 (CXCR4) was analysed in 100 archival breast cancer samples by immunohistochemistry and in two breast cancer microarray datasets of 408 cases. Data were analysed by univariate and multivariate COX regression analyses. CXCL12 and CXCR4 are expressed by epithelial tumour cells and by stromal and endothelial cells. Microarray gene expression analysis and immunohistochemistry revealed that expression of CXCL12 but not of CXCR4 significantly correlates with disease-free and overall survival in oestrogen receptor-positive and -negative cancers. The expression of the oestrogen receptor a and that of CXCL12 do not correlate. CXCL12 is a strong, independent prognostic marker. We propose that saturation of the receptor through autocrine CXCL12 production reduces chemotaxis towards CXCL12-releasing metastasis target tissues. (C) 2009 Elsevier Ltd. All rights reserved.