Chemokine receptor CXCR4 expression in breast cancer as a potential predictive marker of isolated tumor cells in bone marrow

Abstract

Interactions between the CXCR4 chemokine receptor in breast cancer cells and the ligand CXCL12/SDF-1alpha are thought to play an important role in breast cancer metastases. In this pilot study, CXCR4 expression along with other biomarkers including HER2-neu and EGFR, were measured in primary tumor samples of patients with operable breast cancer to test whether any of these biomarkers alone and in combination could indicate breast cancer with high likelihood of metastasizing to bone marrow. Cytokeratin (CK) positive cells in bone marrow were identified by flow-cytometry following enrichment with CK 7/8 antibody-coupled magnetic beads. Primary tumors (n = 18) were stained with specific antibodies for CXCR4, HER2-neu, EGFR, and PCNA using an indirect avidin-biotin horseradish peroxidase method. The majority of the patients had T2/T3 tumors (72%), or lymph node involvement (67%) as pathologic characteristics that were more indicative of high-risk breast cancer. High CXCR4 cytoplasmic expression was found in 7 of 18 patients (39%), whereas 6 of 18 patients (33%) were found to have CK positivity in bone marrow. The median number of CK(+) cells was 236 (range, 20-847) per 5 x 10(4) enriched BM cells. The presence of CK(+) cells in bone marrow was found to be associated with increased expression of CXCR4 alone or in addition to EGFR and/or HER2-neu expression (P = 0.013, P = 0.005, and P = 0.025, respectively) in primary tumors. Furthermore, three patients with high CK positivity (>236 CK(+) per 5 x 10(4) enriched bone marrow cells) in bone marrow exclusively expressed high levels of CXCR4 with EGFR/HER2-neu (P = 0.001). Our data suggest that high CXCR4 expression in breast cancer may be a potential marker in predicting isolated tumor cells in bone marrow. CXCR4 coexpression with EGFR/HER2-neu might further predict a particular subset of patients with high CK positivity in bone marrow.

Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion

“…Because CXCR4 overexpression and p53 mutations are common in cancers, our study suggests a link between these two major signaling pathways involved in cancer progression (Vousden and Lu, 2002;Balkwill, 2004). In breast cancer, CXCR4 expression increases progressively with increasing malignant potential and higher expression is associated with lymph node positivity, hormone receptor negativity, Her2 overexpression and poor survival (Cabioglu et al, 2005;Salvucci et al, 2005). These studies, however, did not compare CXCR4 expression with p53 status.…”

Topotecan inhibits cancer cell migration by down-regulation of chemokine CC motif receptor 7 and matrix metalloproteinases

“…Cells expressing CXCR4 and CCR7 usually metastasize to organs and tissues and secrete respective chemokines, such as SDF-1 and CCL21 [10,11] . Subsequently, we examined the effect of TPT on CXCR4 and CCR7 expression.…”

“…Recent studies have revealed that cancer cells can respond to chemokine stimuli through expression of their respective receptors [6] , altering cancer cell invasive and metastastic properties. Elevated levels of CXCR4 and CCR7 in breast carcinoma are significantly associated with increased malignancy, advanced disease and poor prognosis [7][8][9][10][11] . In breast cancer, CXCR4 expression increases progressively with increasing malignant potential [10] , and CCR7 is associated with lymph node metastasis [11] .…”

“…Elevated levels of CXCR4 and CCR7 in breast carcinoma are significantly associated with increased malignancy, advanced disease and poor prognosis [7][8][9][10][11] . In breast cancer, CXCR4 expression increases progressively with increasing malignant potential [10] , and CCR7 is associated with lymph node metastasis [11] . In melanoma, the recruitment of CCR7-positive cancer cells by CCL21 also leads to lymph nodes metastasis [12] .…”

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

“…Chemokine receptors, including CXCR4 have a critical role in metastasis, and that CXCR4, in particular, is a key receptor in the crosstalk between tumor cells and their environment (Burger and Kipps, 2006). CXCR4 expression increases progressively with increasing malignant potential, and higher expression is associated with lymph node positivity, hormone receptor negativity, Her2 overexpression and poor survival in breast cancer (Cabioglu et al, 2005;Mehta et al, 2007), and that CXCR4 can act as a biomarker for metastasis (Cabioglu et al, 2005). Interestingly, CXCR4 has been shown to be regulated by NF-kB (Palkowitsch et al, 2008) and p53 (Mehta et al, 2007).…”