Flash Talk and Poster Presentation 35th Lorne Cancer Conference 2023

Dissecting the pleiotropic roles of subcellular c-Jun NH-Terminal Kinase in mammary development and breast cancer progression (#15)

Yolande O'Donnell 1 2 , Joseph Powell 1 2 , Thomas Cox 1 2 , Sharissa Latham 1 2 , David Croucher 1 2
  1. Garvan Institute of Medical Research, Cronulla, NSW, Australia
  2. School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia

The c-Jun NH-Terminal Kinase (JNK) is known to be a key regulator of breast cancer metastasis, and is 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, we aim to undertake a more elegant approach 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 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 a number of novel in vivo models that allow discrete comparisons between cytoplasmic and nuclear JNK activity in both native breast, and tumour tissues.

Utilising both orthotopic and genetically engineered mouse models we have demonstrated that cytoplasmic JNK is essential for metastatic progression, whereas nuclear JNK is critical for the maintenance of normal mammary ductal architecture. Single-cell RNA sequencing technologies have also been applied to dissect the transcriptional effect of JNK inhibitors in these models. Additionally, our in vivo results have been recapitulated in complementary three-dimensional in vitro assays using a panel of breast cancer and mammary epithelial cell lines to further characterize the functional roles of these two opposing JNK pools. 

Now, these established models are being used in our drug discovery pipeline to screen novel JNK targeting agents, assessing their suitability as clinically viable treatments for metastatic breast cancer patients.