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Clinical Cancer Research Vol. 11, 5686-5693, August 15, 2005
© 2005 American Association for Cancer Research

Human Cancer Biology

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

Neslihan Cabioglu1, M. Sertac Yazici1, Banu Arun2, Kristine R. Broglio3, Gabriel N. Hortobagyi2, Janet E. Price1 and Aysegul Sahin4

Authors' Affiliations: Departments of 1 Cancer Biology, 2 Breast Medical Oncology, 3 Bioistatistics, and 4 Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Aysegul A. Sahin, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 85, Houston TX 77030. Phone: 713-794-1500; Fax: 713-745-5709; E-mail: asahin{at}mdanderson.org.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
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) T1 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% versus 1.2%, 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.

Tumor size is the most important variable used in current clinical practice to predict lymph node involvement in breast cancer (1–3). Biological markers that can predict lymph node metastases have been a subject of great interest in the efforts to limit the number of complete axillary dissections, especially in patients with small (T1) breast cancers. Although many potential biological markers have been investigated for their value in predicting lymph node metastases, only a limited number have shown a clinically relevant association with such metastases. For example, stimulation of intratumor lymphangiogenesis with growth factors, such as vascular endothelial growth factor-C, has been shown to be associated with lymph node metastases in various cancers (4, 5). Determination of such predictive molecular markers related to lymph node metastasis might also be important for understanding the differential metastatic dissemination of cancer cells.

Recent studies (6–11) have suggested that interactions between the chemokine receptors in breast cancer cells and their ligands in host organs may play a role in malignant dissemination and progression. The chemokine receptors CXCR4 and CCR7 are expressed in some human breast cancer cells in both primary breast tumors and metastases (6). The CXCR4 ligand CXCL12/SDF-1{alpha} was found to be expressed in liver, bone marrow, lung, and lymph nodes, whereas the CCR7 ligand CCL21 was highly expressed in lymph nodes (6). Furthermore, metastasis of breast cancer cells to regional lymph nodes and lung in immunodeficient mice were inhibited by a neutralizing antibody against CXCR4 (6). An increased expression of CCR7 has also been shown in primary tumors of patients with lung cancer (12), esophageal cancer (13), and gastric cancer (14) with lymph node metastases. High diffuse CXCR4 expression was reported by Kato et al. (15) to be associated with the presence of an increased number of metastatic lymph nodes in lymph node–positive breast tumors. However, the number of patients with lymph node positivity was limited, and the CXCR4 positivity was not assessed according to the pattern of the staining (i.e., nuclear versus cytoplasmic). Therefore, it is difficult to conclude from their study that there is a possible association between CXCR4 expression and lymph node metastases in breast cancer.

HER2-neu is a well-known biomarker associated with increased metastatic potential in breast cancer. However, the value of HER2-neu overexpression in predicting lymph node metastasis is controversial. Some studies (16, 17) have found an association between HER2-neu overexpression and lymph node involvement, whereas other studies found no association (3, 18–21). We recently showed a crosstalk between CXCR4 and HER2-neu via HER2-neu transactivation by the SDF-1{alpha}/CXCR4 axis (22). Therefore, we studied the differential expression of CXCR4, HER2-neu, and CCR7 in T1 lymph node–positive and lymph node–negative breast cancers to evaluate whether these markers could predict axillary lymph node status and the extent of lymph node metastasis.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Institutional Review Board approval was obtained for the study. Sections of paraffin-embedded tissue samples were provided by the Breast Tumor Bank of the University of Texas M. D. Anderson Cancer Center from patients with T1 (≤2 cm) lymph node–negative (n = 99) and lymph node–positive (n = 98) breast cancers. All patients had lymph node surgery in M. D. Anderson Cancer Center, and their lymph nodes were evaluated by routine histologic evaluation of H&E sections. The median tumor size was 1.3 cm (range, 0.3-2 cm). Modified Black's nuclear grading system was used to evaluate the nuclear grade of the tumors.

Immunohistochemical analysis. Immunohistochemical staining by the avidin-biotin complex method was used to assess CCR7, CXCR4, and HER2-neu. Briefly, after deparaffinization of 5 µm tissue sections, 0.3% H2O2 in PBS for CXCR4 and HER2-neu, or in methanol for CCR7, was used to block endogenous peroxidase activity in the samples. Nonspecific binding was blocked by incubation in protein blocking solution containing 5% normal horse serum and 1% normal goat serum in PBS for 20 minutes at room temperature. Sections were incubated with a primary antibody for CXCR4 (44173.111, IgG2b; R&D Systems, Minneapolis, MN) at 1:150 dilution, and for CCR7 (2H4, IgM; BD Biosciences, San Diego, CA) at 1:100 dilution, both for 18 hours at 4°C. Color was developed with diaminobenzidine after incubation with a rat anti-mouse–IgG2b–horseradish peroxidase (Serotec, Inc., Raleigh, NC) for CXCR4, and with a goat anti-mouse–IgM–horseradish peroxidase (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) for CCR7. Sections were then counterstained with hematoxylin. For HER2-neu, antigen retrieval by microwave was required before incubation with the primary antibody (clone AB8, NeoMarkers, Lab Vision Corporation, Fremont, CA) at 1:300 dilution at room temperature.

Evaluation of the staining for CXCR4 and CCR7. The intensity, staining percentage, and pattern of staining (nuclear and cytoplasmic) were assessed for CXCR4 and CCR7. The intensity was scored as low, moderate, and strong compared with background staining. The percentages of positive cells were estimated by calculating the ratio of the positively stained invasive tumor cells to the total invasive tumor cells. Nuclear versus cytoplasmic location of expression was also noted in each sample. The staining patterns of tumors for CXCR4 and CCR7 were defined as high cytoplasmic expression or predominantly nuclear expression by using the criteria in Table 1. The expression patterns were correlated with lymph node status and with other markers, including nuclear grade and estrogen receptor/progesterone receptor and HER2-neu status of the tumor. Furthermore, estrogen and progesterone receptors were considered positive if the nuclear staining was >5%. HER2/neu was considered positive in the statistical analyses if >10% of the tumor cells showed a complete and strong membranous staining (3+).


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  		Table 1. Consideration of positivity of chemokine receptors

 
Statistical analysis. The SPSS 10.1 software package (SPSS, Inc., Chicago, IL) was used for statistical analysis. Categorical variables were evaluated by the two-tailed {chi}2 test or two-tailed Fisher's exact test. P < 0.05 was considered statistically significant. Factors that were significantly associated with lymph node metastasis were further evaluated by multivariate logistic regression analysis. The sensitivity and specificity were also estimated for each marker to evaluate its clinical relevance in the assessment of lymph node status.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Staining patterns of CXCR4 and CCR7. In our series, the predominant staining pattern of CXCR4 was cytoplasmic staining with a nuclear component occurring in 62% of the tumors (Fig. 1C). The other staining patterns were as follows: no staining (10%; Fig. 1A), nuclear only (13%; Fig. 1B), and cytoplasmic only (15%; Fig. 1D). In contrast, most tumors expressed cytoplasmic CCR7 (57%; Fig. 2D). Other staining patterns for CCR7 were no staining (22%; Fig. 2A), nuclear staining only (3%; Fig. 2B), and cytoplasmic staining with a nuclear component (18%; Fig. 2C). In addition to staining of the tumor cells, staining for CXCR4 and CCR7 occurred in nonneoplastic tissue adjacent to tumor cells, most notably in adipocytes, perivascular stromal cells, and inflammatory cells.



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  		Fig. 1. Breast tumor samples with negative staining for CXCR4 (A), CXCR4 expression with predominantly nuclear staining pattern (B), CXCR4 expression with nuclear and cytoplasmic staining pattern (C), and CXCR4 expression with high cytoplasmic staining pattern (D). E and F, CXCR4 expression with high cytoplasmic staining pattern in a breast cancer with metastatic involvement in more than four lymph nodes. F, HER2-neu coexpression in the same breast cancer sample.

 


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  		Fig. 2. Breast tumor samples with negative staining for CCR7 (A), CCR7 expression with predominantly nuclear staining pattern (B), CCR7 expression with nuclear and cytoplasmic staining pattern (C), and CCR7 expression with high cytoplasmic staining pattern (D).

 
Factors associated with lymph node metastasis. Lymph node–positive tumors more frequently showed 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 lymph node–negative tumors. Although an increased frequency of CXCR4 positivity (11.2% versus 5.1%, P = 0.113) and high nuclear grade (32.3% versus 21.2%, P = 0.08) was observed in lymph node–positive tumors, these associations did not reach the statistical significance (Table 2). In contrast, predominantly nuclear staining patterns for CXCR4 and CCR7 occurred more commonly in the lymph node–negative group (Table 2). Multivariate logistic regression analysis identified high cytoplasmic CCR7 (odds ratio, 2.6; 95% confidence interval, 1.1-6.6, P = 0.037) and HER2-neu (odds ratio, 2.4; 95% confidence interval, 1.0-5.6, P = 0.05) expressions as predictors of lymph node metastasis, when cytoplasmic CCR7, HER2-neu, and CXCR4 with predominantly nuclear staining pattern were put into the model.


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  		Table 2. Factors associated with lymph node metastases

 
When all three biomarkers (cytoplasmic CCR7, cytoplasmic CXCR4, and HER2-neu) were utilized together, 50% of lymph node–positive tumors highly expressed one of these biomarkers compared with 18.8% of the lymph node–negative tumors (P = 0.0001). Furthermore, 30.2% of lymph node–positive tumors highly expressed one of the chemokine receptors, CCR7 or CXCR4, versus 12.5% of lymph node–negative cancers (P = 0.003).

The estimated sensitivity and specificity of each biomarker for predicting lymph node positivity is shown in Table 3. The specificities of CXCR4, CCR7, and HER2-neu for predicting lymph node positivity were relatively high, ranging from 91% to 95%. However, estimated values for sensitivity ranged from 11% to 22%. Parallel to the results above, the use of both chemokine receptors (CCR7 and CXCR4) or of the three biomarkers (CXCR4, CCR7, and HER2-neu) increased the sensitivity for detecting the lymph node positivity but decreased the specificity compared with using each biomarker alone (Table 3).


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  		Table 3. Sensitivity and specificity for CXCR4, CCR7, and HER2-neu to predict lymph node positivity

 
When factors associated with the number of lymph nodes involved were examined among lymph node–positive tumors, high cytoplasmic CXCR4 coexpressed with HER2-neu overexpression was the only factor that was significantly increased in tumors with four and more lymph nodes involved (Table 4; Fig. 1E-F). A decrease in the predominantly nuclear expression pattern of CXCR4 was also observed in tumors with extensive lymph node metastases, but this association did not reach the statistical significance.


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  		Table 4. Factors associated with the extent of lymph node involvement (>4) among patients with lymph node positivity

 
Associations of other variables with CXCR4 and CCR7 expression. Associations of nuclear and cytoplasmic expression patterns of CXCR4 and CCR7 with other variables, including nuclear grade, estrogen receptor, progesterone receptor, and HER2-neu overexpression, were shown in Table 5. Tumors with high cytoplasmic CXCR4 expression were more likely to have a high nuclear grade but less likely to be estrogen receptor–positive compared with tumors with low cytoplasmic CXCR4. In contrast, tumors with predominantly nuclear CXCR4 expression were less likely to be high nuclear grade and to overexpress HER2-neu. No other significant associations were found between different expression patterns of CXCR4 or CCR7 and other variables (Table 5).


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  		Table 5. Correlations of factors with CXCR4 and CCR7 expressions

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this study, we investigated whether the chemokine receptors CXCR4 and CCR7, novel biomarkers that were recently found to be associated with increased metastatic potential in breast cancer in in vitro and animal studies (6–11), could predict the presence and extent of breast cancer metastases in axillary lymph nodes. For this purpose, a series of exclusively T1 invasive breast cancers with and without lymph node metastases was studied to evaluate the biological significance of CXCR4 and CCR7 in lymph node metastasis without the confounding effect of tumor size on the results. Our findings showed that cytoplasmic CCR7 and HER2-neu overexpression in small breast cancers are significant predictive biomarkers of lymph node metastases, whereas CXCR4 coexpression with HER2-neu was an indicator of more extensive lymph node involvement.

Previous studies (23–25) established the role of CCR7 expression in immune cells, such as T cells and dendritic cells, in homing to lymph nodes through afferent lymphatic vessels where its ligand CCL21 is expressed in high levels. There has been increasing evidence in recent literature showing the association between CCR7 expression in different cancer types and lymph node metastases (5, 12–14). Wiley et al. (26) reported that injection of CCR7-transfected B16 melanoma cells into mice increased the detection of tumor cell metastases to draining lymph nodes by 701-fold in comparison with the control group as shown by real-time PCR measuring mRNA for tyrosinase-related protein, a melanocyte-specific enzyme. An increased expression of CCR7 has been shown in lymph node–positive tumors of patients with non–small cell lung cancer (12), esophageal cancer (13), and gastric cancer (14). Up-regulation of CCR7 was also shown in metastatic cell lines and tumor-containing metastatic lymph nodes of squamous cell cancer of the head and neck that preferentially metastasize to regional lymph nodes with low rates of distant metastases (27). Furthermore, Muller et al. (6) showed increased chemotaxis and chemoinvasion of breast cancer cells toward CCL21, the ligand for CCR7, gradients indicating that CCR7/CCL21 interactions may also play a role in breast cancer metastases to lymph nodes. In concordance with these observations and previous studies in other cancer types, we showed that high cytoplasmic CCR7 expression in T1 breast cancers was associated with lymph node metastases. The nuclear expression of CCR7 was exclusively observed in lymph node–negative tumors.

Similar to CCR7/CCL21 interactions, CXCL12/SDF-1{alpha}/CXCR4 signaling has been shown to be involved in the establishment of lymph node metastases (6, 28–31). Blades et al. (29) showed CXCL12/SDF-1{alpha}–induced migration of a SDF-1{alpha}–responsive cell line (U937) and human peripheral blood lymphocytes from circulation into human lymph nodes transplanted into severe combined immunodeficient mice. CXCR4 has been found to be up-regulated in oral HNt and B88 lymph node metastatic oral squamous cell cancer cell lines compared with the nonmetastatic cell lines, such as IH cells (30). Moreover, CXCR4 stable transfectants of IH cells frequently metastasized to the cervical lymph node, but not to the distant organs in orthotopic inoculation of nude mice (31). Parallel to these results, an increased expression of CXCR4 has been shown in primary tumors of patients with oral squamous cell cancer with lymph node metastases (32). In another study, Muller et al. (6) showed enhanced chemotaxis of breast cancer cells toward lymph node stromal cell supernatants that could be blocked by an anti-CXCR4 antibody. Treating the mice with this neutralizing anti-CXCR4 antibody also inhibited metastasis to inguinal and axillary lymph nodes in immunodeficient mice after orthotopic injection of MDA-MB-231 breast cancer cells. In the current study, we found an increased high cytoplasmic CXCR4 expression in lymph node–positive tumors that did not reach statistical significance, whereas the nuclear expression of CXCR4 was significantly associated with lymph node negativity. Furthermore, tumors with predominantly nuclear CXCR4 expression were less likely to be high nuclear grade tumors than were tumors with high cytoplasmic CXCR4 expression. Spano et al. (33) similarly reported that strong CXCR4 nuclear staining was associated with a better outcome in patients with early-stage non–small cell lung cancer. Thus, different localization patterns of chemokine receptors, nuclear versus cytoplasmic, seem to have different biological significance for metastatic potential of cancer cells.

A recent study (15) reported that high CXCR4-expressing breast tumors showed more extensive lymph node metastases compared with tumors with low expression. However, this study did not categorize the staining according to the localization pattern of the chemokine receptor. In our study, interestingly, a significant increase of high cytoplasmic CXCR4 coexpression with HER2-neu was observed in tumors with extensive lymph node metastases. We recently showed HER2-neu transactivation by CXCL12/SDF-1{alpha} stimulation of the CXCR4 receptor in breast cancer cell lines (22). This observation raises the interesting question whether coexpression of HER2-neu with high cytoplasmic CXCR4 might enhance the metastatic behavior of breast cancer cells. However, only 2% of the T1 breast cancers in our series showed expression of both high cytoplasmic CXCR4 and HER2-neu. Studies evaluating this expression pattern in more advanced breast cancers to determine if it has significance for prognosis are currently ongoing. Furthermore, Li et al. (34) recently reported a correlation between HER2-neu and CXCR4 expression in human breast tumor samples and showed that HER2-neu enhanced the expression of CXCR4 in breast cancer cell lines. Unlike these findings, we were unable to show a correlation between HER2-neu and high cytoplasmic CXCR4, whereas tumors with predominantly nuclear CXCR4 staining were significantly found to express less HER2-neu in the current study. These discrepancies might be due to the different scoring analyses and due to the lack of classification of the staining according to the localization pattern of CXCR4 (nuclear versus cytoplasmic) in Li et al.'s study.

Our results also showed an association between HER2-neu overexpression and involvement of axillary lymph node metastasis, similar to our findings for CCR7. Controversy still remains regarding whether HER2-neu overexpression predicts lymph node metastasis. Although some studies (16, 17) found a relationship between HER2-neu overexpression and lymph node involvement, others (3, 18–21) found no such association. These different results might be due to variations in techniques (PCR, immunohistochemistry, fluorescence in situ hybridization) or other variations in methods, variations in interpretation or reporting the staining, or heterogeneous patient populations with different tumor sizes (35). In the current study, we considered HER2-neu overexpression as detected by immunohistochemistry 3+, and found a 2.4-fold increased risk for lymph node positivity in HER2-neu–overexpressing cancers.

Although we report an association between the biomarkers investigated in this study (CXCR4, CCR7, and HER2-neu) with the involvement of the lymph nodes, the sensitivities of these markers alone were found to be poor despite their high specificity. It is also worthwhile to address the observation that the combined use of all three biomarkers (CXCR4, CCR7, and HER2-neu) predicted almost half of the tumors in the lymph node–positive group by improving the sensitivity, although a decreased specificity was observed compared with the use of each biomarker alone.

In conclusion, our data suggest that the chemokine receptor CCR7 is a novel marker that is associated with lymph node metastasis in breast cancer. Utilization of additional biomarkers, such as CXCR4 and HER2-neu, further improves the classification of lymph node status, and the coexpression of CXCR4 and HER2-neu may be a biological signature of extensive lymph node metastases. These results indicate that these markers may help to predict lymph node status in patients undergoing sentinel lymph node procedures.


   Footnotes
 
Grant support: Nellie B. Connally Breast Cancer Research Fund.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Part of this study was presented at the American Society of Clinical Oncology Annual Meeting, June 6, 2004. N. Cabioglu is a recipient of the 2004 American Society of Clinical Oncology Merit Award.

Received 1/ 5/05; revised 4/22/05; accepted 5/31/05.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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