As mostly ubiquitously expressed transcription factors, proteins of the NF-kappaB family can control the growth and malignancy of many solid tumors, including pancreatic cancer, via the regulation of expression of a large number of downstream genes that control cell proliferation, survival, stress and immune responses. The full importance of NF-kappaB and STAT3 signaling to cancer development and maintenance has been shown. However, despite extensive characterization of NF-kappaB and STAT3 signaling, the specific functional roles of different members of the NF-kappaB and STAT3 family and their interaction in pancreatic cancer are not completely understood.

B-cell CLL/lymphoma 3 (BCL-3), an atypical member of the Inhibitor of kappa-B (IkappaB) family of proteins, is an established oncogene in hematologic malignancies. It predominantly resides in the nucleus and is not degraded upon NF-kappaB activation. Still, the functional outcome of interaction between BCL-3 and NF-kappaB has been controversial. Specific residues of BCL-3 have been shown to require phosphorylation through AKT, ERK2 and IKK1/2 to act as a transcriptional co-regulator of NF-kappaB.

Aiming to determine the role of BCL-3 in pancreatic cancer, we demonstrate overexpression and hyperphosphorylation of BCL-3 in human and murine PDAC tissues and cell lines. Using various in vivo and in vitro genetic tools our preliminary data reveal that BCL-3 is a novel tumor suppressor, negatively regulating the critical proinflammatory pathway STAT3 and metastasis by averting epithelial-mesenchymal transition. These data altogether indicate an important and previously unrecognized role for BCL-3 in PDAC metastasis, highlight several new aspects of BCL-3 in this disease. Therefore, through the generation of phosphorylation-sites specific mutants we plan to detail the tumor suppressor function of BCL-3 in PDAC and metastasis. Finally, the role of these specific residues of BCL-3 and their interaction with the STAT3 pathway will be investigated.

With all these analysis we aim to determine how this knowledge could be exploited for clinical applications.