title: Inflammatory mediators in breast cancer: coordinated expression of TNFα & IL-1β with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition.
abstract: BACKGROUND
  The inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNFα & IL-1β 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.
  
  
  METHODS
  The expression of CCL2, CCL5, TNFα and IL-1β 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.
  
  
  RESULTS
  CCL2, CCL5, TNFα and IL-1β 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 TNFα & IL-1β 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 TNFα & IL-1β expression. These results suggest progression-related roles for TNFα and IL-1β in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNFα and IL-1β compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNFα (and to some extent IL-1β) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1β acts jointly with other pro-malignancy factors to promote disease relapse.
  
  
  CONCLUSIONS
  Our findings suggest that the coordinated expression of CCL2 & CCL5 and TNFα & IL-1β may be important for disease course, and that TNFα & IL-1β 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.
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Gali
authors.initials: G
authors.lastname: Soria
authors.forename: Maya
authors.initials: M
authors.lastname: Ofri-Shahak
authors.forename: Ilana
authors.initials: I
authors.lastname: Haas
authors.forename: Neora
authors.initials: N
authors.lastname: Yaal-Hahoshen
authors.forename: Leonor
authors.initials: L
authors.lastname: Leider-Trejo
authors.forename: Tal
authors.initials: T
authors.lastname: Leibovich-Rivkin
authors.forename: Polina
authors.initials: P
authors.lastname: Weitzenfeld
authors.forename: Tsipi
authors.initials: T
authors.lastname: Meshel
authors.forename: Esther
authors.initials: E
authors.lastname: Shabtai
authors.forename: Mordechai
authors.initials: M
authors.lastname: Gutman
authors.forename: Adit
authors.initials: A
authors.lastname: Ben-Baruch
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D018613:Microscopy, Confocal; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha