Simple Summary Members of the interleukin (IL)-1 cytokine family exhibit dual functions in the regulation of inflammation and cancer. Recent studies have shown the critical role of IL-36 gamma, the newly identified IL-1 family member, in the regulation of cellular processes implicated in the progression of cancer. Therefore, the underlying mechanism of IL-36 gamma in tumor development is of considerable interest. Here, we identified the pivotal role of IL-36 gamma in the proliferation of breast cancer cells. Consistently, IL-36 gamma was found to promote epithelial cell transformation via the activation of c-Fos, c-Jun, and AP-1 transcription factors, followed by the IL36R-mediated MEK/ERK and JNK/c-Jun cascades. Furthermore, our findings demonstrate the critical role of PIN1 in the regulation of IL-36 gamma-induced mammary gland tumorigenesis. Given the increasing recognition of the relationship between IL-1 cytokines, inflammation, and cancer, the significance of distinct members of the IL-1 cytokine family in the etiology of cancer has been widely researched. In the present study, we investigated the underlying mechanism of the IL-36 gamma/IL-36R axis during breast cancer progression, which has not yet been elucidated. Initially, we determined the effects of IL-36 gamma on the proliferation and epithelial cell transformation of JB6 Cl41 mouse epidermal and MCF7 human breast cancer cells using BrdU incorporation and anchorage-independent growth assays. We found that treatment with IL-36 gamma increased the proliferation and colony formation of JB6 Cl41 and MCF7 cells. Analysis of the mechanism underlying the neoplastic cell transformation revealed that IL-36 gamma induced IL-36R-mediated phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun, resulting in increased c-Fos, c-Jun, and AP-1 activities in JB6 Cl41 and MCF7 cells. Furthermore, the IL-36 gamma-induced tumorigenic capacity of MCF7 cells was considerably enhanced by PIN1, following MEK/ERK and JNK/c-Jun signaling. Interestingly, blocking PIN1 activity using juglone suppressed the IL-36 gamma-induced increase in the anchorage-independent growth of 4T1 metastatic mouse breast cancer cells. Finally, in a syngeneic mouse model, IL-36 gamma-induced tumor growth in the breast mammary gland was significantly inhibited following PIN1 knockout.
