Expression Of SDF-1/CXCR4 In Breast Cancer

Objective:Invasive micropapillary carcinoma(IMPC)of the breast is a newly recognized subtype of breast cancer characterized by a high propensity for lymph node metastasis.The purpose of this study is to investigate the relationship between the features of location,expression pattern and intensity of SDF-1/CXCR4 and lymph node metastasis in IMPC of the breast;To explore the reason and the significance of the lymphocytes infiltration in different tumor microenvironment by comparing SDF-1 expression and its relationship with lymphocytes infiltration in IMPC with that in MC of the breast.To investigate the reason of some IMPC in which dense lymphocyte infiltrating but with poor prognosis;To explore the expression of SDF-1/CXCR4 and their association with clinic-pathological features and lymph node metastasis in human invasive breast carcinoma.Methods:Immunohistochemistry and in situ hybridization were performed to analyze the expression of SDF-1/CXCR4 in IMPC(including primary tumor and lymph nodes of IMPC,and 96 cases of IDC as control group),34 of MC and 120 cases of invasive breast cancer.Pathological features,lymphocytes infiltration and status of lymph node metastasis were examined by microscopic analysis.Results:1.The percentage of IMPC component in the whole tumor was not significantly associated with the extent of lymph node metastasis(P=0.067).In 73 cases of mixed-IMPC,IMPC component are the main source for lymph node metastasis compared with other components in the primary tumor(P＜0.001).2.SDF-1 was mainly expressed in tumor cells(96%)and also in stromal cells (14%),staining scores of which were both correlated with the extent of lymph node metastasis in IMPC(P＜0.05).3.Although SDF-1 mRNA was rarely detected in the endothelial cells,SDF-1 immunostaining on lymphatic vessels(36%of IMPCs)was also associated with nodal involvement(P=0.001)and that on blood vessels(34%)correlated with stromal lymphocyte infiltration in IMPC(P=0.024).4.Cytoplasmic SDF-1 expression in tumor cells and SDF-1 staining on vessels in IMPCs were higher than IDCs(P=0.001;P=0.019).5.51 of the 103 IMPCs contained DCIS as or as a part of nonmicropapillary components,in which significantly higher membranous(P=0.009)but similar cytoplasmic SDF-1 staining(P＞0.05)was found compared with IMPC component.6.CXCR4 was detected in either cytoplasm or nucleus of tumor cells,but only cytoplasmic expression in IMPC was correlated with nodal involvement (P=0.008)and higher than IDC group(P=0.049).7.The degree of cytoplasmic and nuclear CXCR4 expression in primary tumor was significantly higher than that in metastatic foci of the same case(P＜0.001).8.SDF-1 and CXCR4 expression in IMPC component were higher than the internal control in mixed-IMPC(P=0.003;P=0.001).9.In the cases of IMPC with abundant infiltrating lymphocytes(+/++)(n=54),the degree of lymph node metastasis,SDF-1 staining in tumor cell cytoplasma and on vessels,CXCR4 nuclear staining were higer than that in MC group(P＜0.01); No difference of SDF-1 membrane staining and CXCR4 cytoplasmic staining was found between the two.groups(P＞0.05).10.SDF-1 was mainly expressed in tumor cells(both membrane and cytoplasm); Cytoplasmic SDF-1 expression in lymph node-positive group was higher than that in node-negative group,and the level of which was correlated with the number of nodal involvement,TNM stages,histological grades,tumor diameter and ER status(P＜0.05).11.CXCR4 was also mainly expressed in tumor cells(both nuclei and cytoplasm); Cytoplasmic SDF-1 expression in lymph node-positive group was higher than that in node-negative group,and the level of which was correlated with the number of nodal involvement,TNM stages,histological grade,tumor diameter and HER-2 status(P＜0.05),but the nuclear expression was only correlated with PR status(P＜0.001).12.The cytoplasmic CXCR4 was correlated with SDF-1 expression positively (P＜0.01).Conclusion:1.The biological behavior of IMPC is not dependent on the percentage of IMPC components in the whole tumor.2.High expression of SDF-1/CXCR4 might be one of the molecular characteristics of IMPC and facilitate lymphatic metastasis.3.SDF-1 located in tumor cells and on vessels,cytoplasmic staining pattern of SDF-1 and CXCR4 may be the key factors that influence the extent of lymph node metastasis in IMPC.4.The significance of lymphocyte infiltrating for prognosis might be different.5.Abundant infiltrating lymphocytes which associated with SDF-1 expression in tumor microenvironment of IMPC might he a factor promoting lymph node metastasis.6.The difference of SDF-1 expression in the two types of breast carcinoma might be the key factor leading to their different prognosis.7.The potential value of SDF-1 and CXCR4 as biomarkers for diagnosis and for predicting lymph node metastasis and a potential therapeutic target in invasive breast carcinoma,but different location in tumor microenvironment and staining patterns may signify different features of tumors.