Breast cancer is the most commonly diagnosed cancer in women worldwide, and an unmet clinical need exists for novel approaches to target cancers refractory to current treatments. We have discovered that conditionally activating ROCK, the major effector of the Rho-ROCK signalling pathway, in a mouse model of breast cancer (PyMT) significantly enhances mammary tumour burden compared to mice expressing a kinase-dead (KD) version of ROCK. Similarly, blocking ROCK activity by administration of pharmacologic inhibitors or a siRNA approach significantly reduces tumour burden. Taken together with our observations that ROCK is progressively activated in human breast cancers, these results suggest that the Rho-ROCK signalling pathway has a causal role in breast cancer progression.
Interestingly, murine mammary tumours in which ROCK had been conditionally activated (ROCK-PyMT) exhibited a larger number of cancer-associated fibroblasts (CAFs) compared to that in control KD-PyMT tumours. CAFs derived from ROCK-PyMT tumours, or those exposed to culture medium conditioned by ROCK-PyMT tumour cells, were more migratory and promoted tumour growth from orthotopically co-injected cancer cells when compared to CAFs from KD-PyMT tumours or those exposed to culture medium conditioned by KD-PyMT tumour cells. Our findings strongly suggested that ROCK regulates breast cancer progression by influencing the cancer-promoting properties of CAFs via fibroblast-educating paracrine signalling mediators. By analysing the secretome of ROCK-PyMT mammary tumour cells, we have now identified that the protein Creld2, secreted downstream of ROCK activation, enhances the cancer-promoting functions of CAFs both ex vivo and in vivo.
By interrupting this signalling between breast cancer cells and their microenvironment, we aim to develop therapeutic strategies that normalise the tumour microenvironment as a novel breast cancer intervention.