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Abstract 4600: IL-22 is specifically required for malignancy in breast cancer: A potential target to control cancer metastasis

IL-22 is important for proliferation and progression of various epithelial cancers. However, in breast cancer, the current knowledge of IL-22 function is based on cell line models and lacks information on stage-specific involvement of IL-22 in multistage pathogenesis of disease. Here, we investigated whether IL-22 expression in the tumor microenvironment (TME) is a stage-specific requirement and if its inhibition can affect that specific stage of cancer progression. We show that the absence of IL-22 in TME did not hinder the initiation and proliferation of cancer but inhibited the invasion and metastasis of cancer. The influence of IL-22 on hyperplasia, adenoma, early carcinoma and late carcinoma stages of cancer was investigated using IL-22 -/- /MMTV-PyMT spontaneous breast cancer mouse model. IL-22 levels were evaluated at these stages of cancer progression and validated in stage-specific specimens of human breast cancer. A variety of histopathological, in vivo and in vitro proliferation, migration, invasion and gene expression assays were performed on tumor tissues and purified epithelial cells. Results showed that IL-22 was absent in TME during initiation and hyperplasia stages of breast cancer. It was expressed during early carcinoma and significantly increased as tumor progressed to malignant stage. In human samples, IL-22 was poorly expressed in high and low grade ductal carcinoma in situ . However, it was significantly higher in invasive or metastatic carcinoma compared to ductal carcinoma in situ . Histological examinations revealed an inhibition in the malignant transformation of epithelial cells during invasion stage in IL-22 -/- tumors. No difference was observed in initiation and hyperplasia stages of cancer between IL-22 -/- and control mice. Ex vivo treatment of IL-22 increased the migration and invasion, but not the proliferation, of purified epithelial cancer cells. RNAseq analysis of premalignant stage epithelial cells revealed down regulation in genes associated with EMT (Epithelial to Mesenchymal Transition) pathway in IL-22 -/- mice. These results show that, in breast cancer, IL-22 is not essential for cell proliferation but it is necessary for malignant transformation of cancer cells which is the critical stage for metastasis. Inhibition of IL-22 can hinder cancer cell malignancy and therefore, it can be an effective therapeutic target to control breast cancer metastasis. Citation Format: Gajendra K. Katara, Arpita Kulshrestha, Sylvia Schneiderman, Safaa Ibrahim, Mahmood Bilal, Valerie E. Riehl, Kenneth D. Beaman. IL-22 is specifically required for malignancy in breast cancer: A potential target to control cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4600.