Elucidating the role of tumour microenvironment in breast cancer metastasis

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Breast cancer is the most common cancer in women, which has a high mortality rate in the UK. Tumour metastasis from breast cancer is associated with a poor prognosis due to its aggressiveness and limited treatment options. Metastasis is divided into discrete biological steps including endothelia-mesenchymal transition (EMT), invasion, intravasation, circulation, extravasation, and colonization. The unique interaction between breast cancer cells and the unique microenvironment of distant organs further promotes tumour metastasis. However, detailed molecular mechanisms of this complex multi-step processes are still poorly understood. There is therefore a critical need to understand the biology of this pathogenesis to find a new and more effective treatment in clinic.

The v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) is a hypoxia-regulated gene, which we have previously demonstrated as a crucial factor in tumour invasion and metastasis. MAFF is a bZIP transcription factor that belongs to the small MAF family, including MAFF, MAFK and MAFG. Small MAF proteins lack transactivation domains and form homodimers or heterodimers with the CNC family (NF-E2, NRF1, NRF2, NRF3) and BACH family proteins (BACH1 and BACH2). The functional role of small MAF proteins is critically dependent on the abundance of these binding partners. In our study, we have found that in breast cancer, which expresses low levels of NRF2 protein, MAFF regulates invasion and metastasis through IL11-STAT3 pathways after forming a heterodimer with BACH1. Furthermore, high expression of MAFF is significantly correlated with poor patient survival specifically in basal-like breast cancer. In this project our aims will be to further investigate the crosstalk with MAFF and tumour microenvironment and how their interactions enhance metastatic behaviour of tumour cells. With extensive work using basic science to preclinical science techniques, we will interrogate the role of MAFF in tumour metastasis as a potentially targetable mechanism in breast cancer.

Training Opportunities

The student will be trained to perform basic cell and molecular biology as well as mouse work including western blot, qRT-PCR, invasion assay, chromatin immunoprecipitation, mouse xenograft studies (breast cancer orthotopic model), and immunohistochemistry. In addition, through weekly lab meeting, journal clubs and departmental seminar, skills for presentation, data management, and scientific writing will be trained.