Abstract
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.
Highlights
Breast cancer is the most common malignancy in women (Bray et al, 2018)
To extend our knowledge of the function of IL-22 in breast cancer, we developed an IL-22 knockout spontaneous breast cancer mouse model
polyomavirus middle T antigen (PyMT) mouse model is considered a good model to study the breast tumorigenesis as it closely reflects the biology of human breast cancer
Summary
Breast cancer is the most common malignancy in women (Bray et al, 2018). The majority of breast cancer-associated deaths (90%) are caused by metastases of cancer cells rather than primary tumors (Weigelt et al, 2005). Metastasis is a complex and multistep process that involves detachment of specialized cancer cells from the primary tumor, invasion of surrounding stroma, entry into the circulation, and colonization in distant organs.
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