The c-Jun NH-Terminal Kinase (JNK) is known to be a key regulator of breast cancer metastasis, and is therefore considered an attractive therapeutic target for metastatic breast cancer. However, as JNK also plays an essential role in normal tissue function, the systemic targeting of JNK has not yielded successful translation to the clinic. As such, a more elegant approach is required to dissect the pleiotropic functions of JNK and to develop treatments that maintain normal tissue function, while specifically targeting the tumour promoting functions of JNK.
Through immuno-histochemical analyses of breast cancer patient cohorts, we now demonstrate that there are two prognostically distinct subcellular JNK networks; a nuclear and a cytoplasmic JNK pool. To dissect the roles of these discrete JNK pools, we have adopted an orthotopic mouse model that allows discrete comparisons between cytoplasmic and nuclear JNK activity in breast tissue. Utilising these in vivo models and single-cell RNA-sequencing we have demonstrated that cytoplasmic JNK is essential for metastatic progression, whereas nuclear JNK is critical for the maintenance of normal mammary ductal architecture and physiological function. These results have also been recapitulated in complementary three-dimensional in vitro assays using a panel of breast cancer cell lines that express inducible subcellular JNK inhibitors.
These models will now be utilized to further dissect the specific mechanisms by which the spatially separated JNK networks act and will enable the testing and development of clinically viable strategies for the treatment of metastatic breast cancer.