The inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNFalpha & IL-1beta were shown to contribute to breast cancer development and metastasis. In this study, we wished to determine whether there are associations between these factors along stages of breast cancer progression, and to identify the possible implications of these factors to disease course.

The expression of CCL2, CCL5, TNFalpha and IL-1beta was determined by immunohistochemistry in patients diagnosed with: (1) Benign breast disorders (=healthy individuals); (2) Ductal Carcinoma In Situ (DCIS); (3) Invasive Ducal Carcinoma without relapse (IDC-no-relapse); (4) IDC-with-relapse. Based on the results obtained, breast tumor cells were stimulated by the inflammatory cytokines, and epithelial-to-mesenchymal transition (EMT) was determined by flow cytometry, confocal analyses and adhesion, migration and invasion experiments.

CCL2, CCL5, TNFalpha and IL-1beta were expressed at very low incidence in normal breast epithelial cells, but their incidence was significantly elevated in tumor cells of the three groups of cancer patients. Significant associations were found between CCL2 & CCL5 and TNFalpha & IL-1beta in the tumor cells in DCIS and IDC-no-relapse patients. In the IDC-with-relapse group, the expression of CCL2 & CCL5 was accompanied by further elevated incidence of TNFalpha & IL-1beta expression. These results suggest progression-related roles for TNFalpha and IL-1beta in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNFalpha and IL-1beta compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNFalpha (and to some extent IL-1beta) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1beta acts jointly with other pro-malignancy factors to promote disease relapse.

Our findings suggest that the coordinated expression of CCL2 & CCL5 and TNFalpha & IL-1beta may be important for disease course, and that TNFalpha & IL-1beta may promote disease relapse. Further in vitro and in vivo studies are needed for determination of the joint powers of the four factors in breast cancer, as well as analyses of their combined targeting in breast cancer.

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