CCR7 and CXCR4 as Novel Biomarkers Predicting Axillary Lymph Node Metastasis in T1 Breast Cancer

Abstract

Purpose:The chemokine receptors CCR7 and CXCR4 have been shown to play an important role in cancer metastasis.We therefore studied the differential expression of CCR7 and CXCR4, along with that of the biomarker HER2-neu, to evaluate whether these biomarkers could predict axillary lymph node metastasis in breast cancer. Experimental Design: Biomarker expression levels were evaluated using paraffin-embedded tissue sections of lymph node^negative (n = 99) and lymph node^positive (n = 98) T 1 breast cancer by immunohistochemical staining. Results: Lymph node^positive tumors showed higher rates of high cytoplasmic CCR7 staining (21.5% versus 8.5%, P = 0.013) and HER2-neu overexpression (21.5% versus 9.3%, P = 0.019) than did lymph node^negative tumors. Similarly, high cytoplasmic CXCR4 expression occurred more commonly in lymph node^positive tumors (11.2% versus 5.1%, P = 0.113). In contrast, predominantly nuclear CXCR4 staining was more likely to be found in lymph node^negative tumors (54.5% versus 37.8%, P = 0.018). Furthermore, cytoplasmic CXCR4 coexpressed with HER2-neu was the only factor associated with involvement of four or more lymph nodes (16.7% versus1.2%, P = 0.04) among lymph node^positive tumors.When all three biomarkers (CCR7, CXCR4, HER2-neu) were utilized together, 50.0% of lymph node^positive tumors highly expressed one of these biomarkers compared with 18.8% of the lymph node^negative tumors (P < 0.0001). Conclusions:Our results suggest that the chemokine receptor CCR7 is a novel biomarker that can predict lymph node metastases in breast cancer. Utilization of additional markers, such as CXCR4 and HER2-neu, further improves the prediction of the presence and extent of lymph node involvement.

Quantitative Real-Time RT-PCR of ITGA7, SVEP1, TNS1, LPHN3, SEMA3G, KLB and MMP13 mRNA Expression in Breast Cancer

“…The accuracy of lymph-node evaluation influences clinicians' choice of the appropriate therapeutic regimen and most likely prognosis (Fisher et al, 1983;Jatoi et al,1999;. In recent years, many sensitive methods have been developed to detect micro-metastasis in lymph nodes, e.g., immunohistochemical (Cabioglu et al, 2005;Denninghoff et al,2008;Thongwatchara et al, 2011;Yenidunya et al,2011) and molecular biological techniques. However, the role of micro-metastasis in clinical outcome is under extensive study.…”

Chemokines in tumor angiogenesis and metastasis

“…The expression of CXCR4 has been reported in more than 23 different types of cancer cell [137]. The accumulating evidence suggests that CXCR4 is an important regulator of breast cancer metastasis and can be predictive of lymph node metastasis [138][139][140]. In experimental studies, treatment of CXCR4-expressing breast cancer cells with neutralizing anti-CXCR4 antibody reduced metastasis to lung in a mouse model [133].…”

“…In oesophageal cancer and melanoma, CXCR4 expression is associated with poor clinical outcome [147,148]. In breast cancer, CXCR4 expression predicted lymph node metastasis [138]. Patients with high CXCR4 expression in NSCLC, colorectal or prostate cancer were more prone to metastasis [149][150][151].…”

“…Recently, it has been reported that CCR7 activation on thyroid carcinoma cell by CCL21 favors tissue invasion and cell proliferation, and therefore may promote thyroid carcinoma growth and lymph node metastasis [172]. CCR7 is a potential marker to predict metastasis in breast and colorectal cancer and is correlated with disease progression [138,166]. In addition, patients with oral and oropharyngeal squamous cell carcinomas that express CCR7 have lower survival rates than those with CCR7-negative tumors [173].…”

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

“…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] .…”