title: Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells.
abstract: BACKGROUND
  Inflammation has been implicated in cancer aggressiveness. As transglutaminase 2 (TG2), which has been associated with inflammatory signaling, has been suggested to play a role in tumor behavior, we propose that TG2 may be an important linker inducing interleukin (IL)-6-mediated cancer-cell aggressiveness, including distant hematogenous metastasis.
  
  
  METHODS
  To investigate the role for TG2 and IL-6, TG2-knocked-down and IL-6-knocked-down cancer cells were generated by using shRNA. Human breast cancer cell xenograft model in highly immunocompromised mice and human advanced breast cancer primary tumor tissue microarrays were used in this study.
  
  
  RESULTS
  IL-6 production in human breast cancer cells was dependent on their TG2 expression level. In vitro tumor-sphere formation was dependent on TG2 and downstream IL-6 production from cancer cells. Primary tumor growth in the mammary fat pads and distant hematogenous metastasis into the lung was also dependent on TG2 and downstream IL-6 expression levels. The effect of TG2 expression on human breast cancer distant metastasis was investigated by analyzing a tissue microarray of primary tumors from 412 patients with their clinical data after 7 years. TG2 expression in primary tumor tissue was inversely correlated with recurrence-free survival (P = 0.019) and distant metastasis-free survival (DMFS) (P = 0.006) in patients with advanced breast cancer. Furthermore, by using public datasets that included a total of 684 breast cancer patients, we found that the combined high expression of TG2 and IL-6 was associated with shorter DMFS, compared with the high expression of IL-6 only (P = 0.013).
  
  
  CONCLUSIONS
  We provide evidence that TG2 is an important link in IL-6-mediated tumor aggressiveness, and that TG2 could be an important mediator of distant metastasis, both in a xenograft animal model and in patients with advanced breast cancer.
authors.affiliation: Laboratory of Immunology, Interdisciplinary Program of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-799, Korea.
authors.forename: Keunhee
authors.initials: K
authors.lastname: Oh
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Ko
authors.forename: Hee Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Ae Kyung
authors.initials: AK
authors.lastname: Park
authors.forename: Hyeong-Gon
authors.initials: HG
authors.lastname: Moon
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002470:Cell Survival / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D019204:GTP-Binding Proteins; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins