Metastasis, the spread of tumour cells from the primary site to other sites within the body, causes the majority of breast cancer-related deaths. It is becoming clearer that the tumour microenvironment, composed of tumour infiltrating cells and the extra-cellular matrix (ECM), plays a critical role in the progression of this disease to the metastatic stage.
The Rho-ROCK signalling pathway is hyper-activated in many epithelial cancers and is associated with progressive and metastatic disease. Our laboratory and others have demonstrated that increased signalling via Rho-associated kinase (ROCK) enhances the production of a tumour-promoting ECM, thereby accelerating disease progression. We have also demonstrated that the molecular chaperone and adaptor protein 14-3-3ζ is a key negative regulator of signalling through ROCK and its deficiency in mice increases tumour size in a model of cutaneous squamous cell carcinoma.
14-3-3 inhibition has been widely proposed as a therapeutic target in cancers including in breast cancer. We are therefore investigating the role of 14-3-3ζ and its association with the Rho-ROCK signalling pathway in a murine model of breast cancer to dissect out the cellular mechanisms underlying 14-3-3ζ function in this cancer type.
Our data suggest a differential role for 14-3-3ζ in regulating cancer cell vs microenvironment processes during mammary tumorigenesis. 14-3-3ζ-deficiency in tumour cells inhibits tumour growth, while 14-3-3ζ-deficiency in the microenvironment enhances tumour growth, likely by both ROCK-dependent and ROCK-independent mechanisms. Our observations have important implications for the targeting of 14-3-3 as a therapeutic approach against breast cancers.