Interleukin‐22 promotes development of malignant lesions in a mouse model of spontaneous breast cancer

Interleukin (IL)‐22 is recognized as a tumor‐supporting cytokine and is implicated in the proliferation of multiple epithelial cancers. In breast cancer, the current knowledge of IL‐22 function is based on cell line models and little is known about how IL‐22 affects the tumor initiation, proliferation, invasion, and metastasis in the in vivo system. Here, we investigated the tumor stage‐specific function of IL‐22 in disease development by evaluating the stage‐by‐stage progression of breast cancer in an IL‐22 knockout spontaneous breast cancer mouse model. We found that among all the stages, IL‐22 is specifically upregulated in tumor microenvironment (TME) during the malignant transformation stage of breast tumor progression. The deletion of IL‐22 gene leads to the arrest of malignant transition stage, and reduced invasion and tumor burden. Administration of recombinant IL‐22 in the TME does not influence in vivo tumor initiation and proliferation but only promotes malignant transformation of cancer cells. Mechanistically, deletion of IL‐22 gene causes downregulation of epithelial‐to‐mesenchymal transition (EMT)‐associated transcription factors in breast tumors, suggesting EMT as the mechanism of regulation of malignancy by IL‐22. Clinically, in human breast tumor tissues, increased number of IL‐22(+) cells in the TME is associated with an aggressive phenotype of breast cancer. For the first time, this study provides an insight into the tumor stage‐specific function of IL‐22 in breast tumorigenesis.