Myb rearrangements in adenoid cystic carcinoma: protagonists or secondary characters?
Adenoid cystic carcinoma (ACC) is both a rare disease (limited scientific data and professional expertise) and a cancer (complex tumour biology and evasion of conventional therapies). Clinical behaviour differs depending on primary tumour site; salivary gland ACC has poorer prognosis than breast ACC. A majority of ACC harbour MYB rearrangements resulting from chromosomal translocations, with the fusion of MYB and NFIB or MYBL1 and NFIB being the most frequent. The role of translocations in tumourigenesis and whether cells from different primary sites respond differently has not been determined. Identification of specific cell types carrying the translocation and location within the tumour microenvironment might enable development of MYB target-therapies. Our main objective is to elucidate the function of MYB rearrangements in normal salivary and mammary gland cells and the expression of the novel fusion genes in salivary gland and breast ACC. Normal human cells will be transfected with MYB-NFIB and MYBL1-NFIB fusion transcripts and fusion negative, fusion positive and combinations of cells will be compared in terms of cell morphology, differentiation, proliferation, migration and invasion. 3D models, more closely mimicking an in vivo tumour, will be compared to monolayer cultures. In situ localisation of MYB-NFIB and MYBL1-NFIB in salivary gland and breast ACC will be assessed using a novel technology, BaseScope. This ambitious research project will determine the consequences of MYB rearrangements using state-of-the-art methods in molecular and cellular biology, genetic and tissue engineering and pathological anatomy. The project has clear translational potential with social, cultural and economic impacts. Transfer of results to other cancers harbouring MYB rearrangements (eg leukaemia, colon cancer) and our methods in assessing other tumours characterised by chromosomal translocations, eg prostate, colorectal and non-small-cell lung cancer, are further outcomes.