The Oestrogen Receptor Positive (ER+) breast cancer subtype accounts for approximately 76% of all breast cancer diagnoses. The c-Jun NH-Terminal Kinase (JNK) is known to integrate signalling from a number of potential breast cancer oncogenes and loss-of-function mutations in upstream regulators of JNK are frequent within this breast cancer subtype. However JNK plays a complex role in breast cancer, it both promotes tumour progression and also prevents cancer in normal tissues.
We have therefore used highly specific, inducible inhibitors within established in vitro models in order to characterise the distinct tumour promoting and tumour suppressing JNK pools in breast cancer. Stable breast cancer and mammary epithelial cell lines expressing these inhibitors have been used in three-dimensional models, and our preliminary data has demonstrated that JNK play a key role in cell colony formation, polarity and chemotherapy response. These results are also recapitulated by the introduction of mutations within upstream JNK regulators.
This project also utilises three key in vivo models to dissect the role of JNK in breast cancer, particularly the role of JNK in primary tumour growth and normal tissue physiology, colonisation of various secondary metastatic sites as well as the development and ongoing function of the mammary gland. In all models immunohistochemistry and immunofluorescence are used to study tissue morphology as well as quantitate changes in signalling pathway activation. In addition to this analysis we are utilising single-cell RNA sequencing in order to analyse the effect of JNK inhibition on the mammary gland, primary tumour and surrounding microenvironment transcriptome.
The JNK protein plays a complex role in breast cancer, both promoting tumour progression and preventing cancer in normal tissues. It is essential to further elucidate these functions as part of our ongoing drug development to ensure that tumour suppression is not disrupted in the presence of candidate oncogenic JNK-targeting drugs.