IL-1β induces IL-6 production and increases invasiveness and estrogen-independent growth in a TG2-dependent manner in human breast cancer cells.
We previously reported that IL-6 and transglutaminase 2 (TG2) were expressed in more aggressive basal-like breast cancer cells, and TG2 and IL-6 expression gave these cells stem-cell-like phenotypes, increased invasive ability, and increased metastatic potential. In the present study, the underlying mechanism by which IL-6 production is induced in luminal-type breast cancer cells was evaluated, and TG2 overexpression, IL-1β stimulation, and IL-6 expression were found to give cancerous cells a hormone-independent phenotype.



Luminal-type breast cancer cells (MCF7 cells) were stably transfected with TG2. To evaluate the requirement for IL-6 neogenesis, MCF7 cells were stimulated with various cytokines. To evaluate tumorigenesis, cancer cells were grown in a three-dimensional culture system and grafted into the mammary fat pads of NOD/scid/IL-2Rγ(-/-) mice.



IL-1β induced IL-6 production in TG2-expressing MCF7 cells through an NF-kB-, PI3K-, and JNK-dependent mechanism. IL-1β increased stem-cell-like phenotypes, invasiveness, survival in a three-dimensional culture model, and estrogen-independent tumor growth of TG2-expressing MCF7 cells, which was attenuated by either anti-IL-6 or anti-IL-1β antibody treatment.



Within the inflammatory tumor microenvironment, IL-1β increases luminal-type breast cancer cell aggressiveness by stimulating IL-6 production through a TG2-dependent mechanism.
Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Transplantation Research Institute, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul, Korea. keunhee1@snu.ac.kr.|PharmAbcine, Inc., #461-8, DaejeonBioventure Town, Jeonmin-dong, Yusung-gu, Daejeon, Korea. keunhee1@snu.ac.kr.
Keunhee
K
Oh
Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Transplantation Research Institute, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul, Korea.
Ok-Young
OY
Lee
Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Transplantation Research Institute, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul, Korea.
Yeonju
Y
Park
Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Transplantation Research Institute, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul, Korea.
Myung Won
MW
Seo
Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Transplantation Research Institute, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul, Korea. dlee5522@snu.ac.kr.
Dong-Sup
0000-0001-8312-2705
DS
Lee
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D009361:Neoplasm Invasiveness; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism
D004967:Estrogens; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
Hormone-independent; IL-1β; IL-6; Luminal-type breast cancer cell; Transglutaminase 2