Exploring Microenvironmental Regulation of Metastasis Through HSP27

As breast cancer develops, it acquires the ability to spread to other locations in the body, a process referred to as ‘metastasis’. This spread follows a certain pattern, partly because of anatomical considerations – the ‘geography of the body’ – but which also depends on whether the new location provides a favourable environment for cancer growth. One of the most important factors in this is CXCR4, a protein on the cancer cell that senses a unique, attractive partner which is specifically enriched in tissues such as lymph nodes, lung and bone marrow. CXCR4 acts as a ‘pilot’ and seeks out its partner to ‘dock’ in those tissues - which unfortunately then become areas of secondary cancer. CXCR4-mediated cellular migration, as it is called, is linked to aggressive behaviour in breast cancer and patient survival. Dr Jonathan Blay and his team have found that the activity of CXCR4 is enhanced by factors in the tumour itself, meaning that breast cancer can promote its own spread. The tumour environment is hostile, so the cancer cell has adapted to being in the ‘rough end of town’, developing features that will help it to escape to other locations and survive. These changes include alterations in stress response or ‘heat-shock’ proteins (HSPs), one of which is called HSP27. Dr Blay has teamed up with Dr Tom MacRae, who is an expert in HSPs. They will investigate how HSP27 links the response to stressful conditions with changes in CXCR4 that may encourage metastasis. This work will be the first step towards a goal of using combined targeting of HSP27/CXCR4 to reduce cancer cell migration and growth, to help control the metastatic spread of breast cancer. 1.Characterize the changes in HSP27 expression, abundance and phosphorylation in breast cancer cells upon exposure to stressors characteristic of the tumour tissue.2.Determine how HSP27 abundance and/or phosphorylation affect cell migration and tissue invasion dependent upon CXCR4 and SDF-1a.3.Identify the structural features of HSP27 required for regulation of cell survival and migration, and determine their relationship to the SDF-1a:CXCR4 axis.