Bcl-3 acts as a proto-oncogene in pancreatic cancer in humans and mice

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Introduction: Despite numerous efforts to develop novel therapies, pancreatic ductal adenocarcinoma (PDAC) has remained one of the most devastating and lethal malignancies worldwide. B-cell chronic lymphatic leukemia protein 3 (Bcl-3) is an atypical member of the ankyrin repeat-containing IκB family of NF-κB inhibitors that was first identified as a candidate proto-oncogene in chronic lymphocytic leukemia. Accumulating evidence reveals that elevated Bcl-3 expression results in increased cell proliferation, cell survival and malignant potential. However, the functional role of Bcl-3 in pancreatic cancer has not been elucidated so far. In this study, we aim to identify whether Bcl-3 impacts pancreatic cancer development and progression in humans and mice. Material and methods: PDAC tissues and cell lines obtained from humans and a Kras G12D mouse model ( KC ) of pancreatic cancer were investigated for Bcl-3 expression. The overall survival of human PDACs expressing high and low levels of Bcl-3 was compared. Further, Bcl-3 was deleted in a Kras G12D mouse model ( KCB ) and tumor incidence, metastases as well as proliferation, and apoptosis in tumor tissues and primary tumor cells of KC and KCB mice were investigated. Pancreatic Intraepithelial Neoplasia (PanIN) in KC and KCB mice at 13 and 24 weeks was analyzed. Results: We show that Bcl-3 is highly expressed in human PDACs and in a KC mouse model of pancreatic cancer, correlating with prognosis and overall survival. Bcl-3 promotes cell growth and cell survival in vivo and in vitro . Further, Bcl-3 leads to acceleration in PanIN progression, tumor development and metastases in a KC mouse model of pancreatic cancer. Conclusions: In summary, our data provide the first insights into the function of Bcl-3 in pancreatic cancer, and indicate that Bcl-3 has an important pro-tumorigenic role in pancreatic cancer development and progression.

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