The Triple Negative Breast Cancer (TNBC) subtype is known to be highly aggressive, leading to large primary tumours and increased metastatic risk. The lack of clinically successful targeted therapies for TNBC means that chemotherapy remains the standard-of-care, although there are no therapeutic options for specifically targeting metastatic TNBC.
The c-Jun NH Terminal Kinase (JNK) has long been considered a critical oncogenic signalling node in TNBC. Although due to the necessity of JNK for many normal processes, tumour suppression and chemotherapy response in other tissues, systemically targeting JNK is unlikely to yield successful translation to the clinic. Instead, we now demonstrate that two spatially distinct JNK network states exist simultaneously within breast cancer cells, with opposing functional and prognostic roles.
While we have shown that nuclear JNK activity is important for maintaining the polarity of breast tissue, we have now used genetically encoded, localisation-specific JNK inhibitors to demonstrate that selective inhibition of cytoplasmic JNK in vivo significantly reduces lung metastasis in an orthotopic MDA-MB-231 model. Functional characterisation of this effect using three-dimensional in vitro models has shown that this selective inhibition of cytoplasmic JNK does not influence cell invasion, but significantly reduces colony formation and promotes anoikis.
Therefore, we have now demonstrated that these two spatially separated JNK network states are functionally distinct. These findings will enable future development of novel therapeutics that target the oncogenic cytoplasmic JNK signalling node in metastatic TNBC patients.