IL-1β induces IL-6 production and increases invasiveness and estrogen-independent growth in a TG2-dependent manner in human breast cancer cells

Keunhee Oh, Ok-Young Lee, Yeonju Park, Myung Won Seo, Dong-Sup Lee

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.