The Oestrogen Receptor Positive (ER+) breast cancer subtype is a highly heterogenous disease and accounts for approximately 76% of all breast cancer diagnoses. Loss-of-function mutations in upstream regulators of the c-Jun NH-Terminal Kinase (JNK) are frequent within this breast cancer subtype, although their function is mostly unknown.
JNK is known to integrate signalling from a number of potential breast cancer oncogenes, as well as having a critical role in tumour suppression. We have previously demonstrated this pleiotropic role of JNK in breast cancer, identifying two prognostically, spatially and functionally distinct JNK pools; a tumour promoting cytoplasmic pool and tumour suppressing nuclear pool. Therefore, using inducible, localisation-specific inhibitors as well as CRISPR mediated-gene editing within established in vivo and in vitro models we have now dissected the role of nuclear JNK signalling in normal mammary epithelia and ER+ breast cancer cells.
This analysis demonstrated that the loss of nuclear JNK activity results in a loss of cell polarity and a subsequent defect in luminal clearing. Furthermore, these effects on nuclear JNK activity and cell polarity are recapitulated by the introduction of mutations within the upstream JNK regulators, MAP3K1 and MAP2K4, which also result in a decreased sensitivity of ER+ breast cancer cells to treatment chemotherapy. Therefore, we have now provided the first functional characterisation of these frequent breast cancer mutations, and also unravelled the subcellular specific actions of JNK signalling in breast cancer.