Triple negative breast cancer (TNBC) patients have the worst outcomes of all breast cancer subtypes due to a lack of targeted therapies and high relapse rates with distant metastases. Given that metastases are the cause of death for the majority of these patients, there is an urgent need for the development of innovative approaches that specifically treat metastatic TNBC to improve patient outcomes.
The c-Jun N-terminal Kinase (JNK) has been identified as a central oncogenic signalling node in TNBC crucial for metastatic disease progression, making it an attractive therapeutic target. However, as JNK is also required to maintain the architecture of normal breast tissue and activate apoptosis in response to chemotherapeutic intervention, it is unlikely that broad-spectrum JNK inhibitors will yield clinical success. As such, alternate approaches are needed to selectively target the oncogenic functions of JNK.
Through immuno-histochemical analysis of breast cancer patient cohorts, we now demonstrate that there are two prognostically distinct subcellular JNK networks; a nuclear and a cytoplasmic JNK pool. Using doxycycline-inducible genetically-encoded localisation specific JNK inhibitors and broad spectrum JNK inhibitors in our adapted orthotopic models, we further reveal that cytoplasmic JNK is essential for metastatic disease progression, whereas nuclear JNK is critical for the maintenance of normal mammary gland architecture. These models provide the first clear demonstration of why JNK inhibitors fail as anti-cancer therapies and have allowed us to directly validate the efficacy of an emerging class of selective oncogenic JNK inhibitors.