CXC chemokines located in the 4q21 region are up-regulated in breast cancer

Abstract

Recent data suggest that chemokines could be essential players in breast carcinogenesis. We previously showed that the CXC chemokine CXCL8 (interleukin-8) was overexpressed in estrogen receptor a (ERa)-negative breast cell lines. Analysis of CXCL8 chromosomal location showed that several CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL4V1, CXCL5, CXCL6, CXCL7, and CXCL8) were localized in the same narrow region (360 kb in size) of chromosome 4. We thus hypothesized that they could belong to the same cluster. Quantification of these chemokines in breast tumors showed that samples expressing high CXCL8 also produced elevated levels of CXCL1, CXCL3, and CXCL5, and displayed low content of ERa. CXCL1, CXCL2, CXCL3, CXCL5, and CXCL8 were co-regulated both in tumors and in breast cancer cell lines. CXCL5 and CXCL8 were mainly produced by epithelial cells, whereas CXCL1, CXCL2, and CXCL3 had a high expression in blood cells. The overexpression of these chemokines in tumor cells was not the result of gene amplification, but rather of an enhanced gene transcription. Our data suggest that high CXCL8 expression in tumors is mainly correlated to activating protein-1 (AP-1) pathway and to a minor extent to NF-kB pathway. Interestingly, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, and CXCL8 chemokines were present at higher levels in metastases when compared with grade I and III biopsies. High levels of CXCL8, CXCL1, and CXCL3 accounted for a shorter relapse-free survival of ERa-positive patients treated with tamoxifen. In summary, we present evidences that multiple CXC chemokines are co-expressed in CXCL8-positive breast tumors. In addition, these chemokines could account for the higher aggressiveness of these types of tumors.

Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines

“…We also observed a modification in the production of tumor CXCL8, which is considered as marker of breast cancer aggressiveness (Bieche et al, 2007). Moreover, CXCL8 could indirectly stimulate VEGF production by 786-O cells as they express the CXCR-2 receptor (Mestas et al, 2005).…”

“…Our hypothesis states that this could be due to the production of redundant angiogenic cytokines. Hence, we have focused on the targeting of VEGF and the cytokines of the CXCL family that have angiogenic and antiangiogenic potency depending on the presence or absence of the amino-acid triplet ELR in their protein sequence (ELR þ CXCL (1,2,3,5,6,7,8) have pro-angiogenic properties, whereas ELRÀCXCL (4, 9, 10) have antiangiogenic properties) (Vandercappellen et al, 2008), as these cytokines may have prognostic value in breast cancer (Bieche et al, 2007). ELR þ CXCL stimulate their G-protein-coupled receptors CXCR-1 and CXCR-2, which leads to the activation of the extracellular signalregulated kinase (ERK) pathway (Vandercappellen et al, 2008).…”

Stemness-Related Transcriptional Factors and Homing Gene Expression Profiles in Hepatic Differentiation and Cancer

“…It has diverse effects on carcinogenesis, according to the tumor microenvironment. CXCL2 relative expression has been found to be low in breast cancer (19) and elevated in an estrogen receptor-positive breast cancer type in another study (20). The same levels of expression have been found in normal and adenocarcinoma samples of the colon (21), while it was significantly elevated in colon cancer compared with normal adjacent tissue, facilitating cancer cell invasion and metastasis, and correlated with an unfavorable outcome in other studies (22,23).…”

Cell Density Regulates Cancer Metastasis Via the Hippo Pathway

“…Moreover, low levels of cytokines were associated with a longer relapse-free patient survival supporting their impact on the aggressiveness of the particular cancer [35]. In mechanistic studies with cultured cells and animal models, cytokines were associated with a more invasive cancer cell phenotype.…”