c-Jun N-terminal Kinase (JNK) is known to be a potent oncogene in numerous cancers, including breast and pancreatic cancer. Although JNK can promote metastatic progression, it is also vital for tumour suppression and apoptotic signalling in a number of tissues. Our immunohistochemical analysis of JNK activity (ppJNK) within breast cancer cohorts has unveiled the mechanism underlying these complex roles to be distinct, subcellular pools of JNK activity. Specifically, JNK activity was predominantly localised to the nucleus in normal breast tissue, but significantly elevated in the cytoplasm of triple-negative tumours. Both the loss of nuclear JNK activity and gain of cytoplasmic JNK activity were independently associated with poorer overall and relapse free survival. Functional assays further demonstrated that nuclear JNK plays an important tumour suppressive role in maintaining normal mammary tissue architecture, whereas cytoplasmic JNK activity is crucial for metastatic outgrowth.
This oncogenic role of JNK has been previously implicated in the progression of pancreatic cancer, prompting us to investigate whether similar patterns of subcellular JNK activity would be observed within Pancreatic Ductal Adenocarcinoma (PDAC). Firstly, utilising two genetically-engineered mouse models of pancreatic cancer (KPflC and KPC) we revealed that nuclear JNK activity within the normal pancreas is progressively lost as tumours progressed to PDAC, which was also associated with an increase in cytoplasmic JNK activity. Furthermore, analysis of the ICGC patient cohort demonstrated that a loss of nuclear JNK activity is common within PDAC tumours, while cytoplasmic JNK activity is constitutively elevated. This data indeed suggests that the dual JNK network states found within breast tissue are functionally relevant in pancreatic cancer, which we will further investigate using localisation-specific inhibitors of JNK activity.