Poster Presentation 32nd Lorne Cancer 2020

Uncovering the role of alternative splicing in mammary gland development and breast cancer (#309)

Michael Milevskiy 1 2 , Lexie Prokopuk 1 2 , Jaynish Shah 3 4 , Ulf Schmitz 3 4 , Shirley Song 1 , Yunshun Chen 1 2 , Gordon Smyth 1 2 , John Rasko 3 4 5 , Geoffrey Lindeman 1 2 , Jane Visvader 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
  3. Centenary Institute, University of Sydney, Sydney, NSW, Australia
  4. Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  5. Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, NSW, Australia

Breast cancer is the most prevalent tumour found in women in Australia. Breast tumours are highly heterogenous and are classified into six subtypes based on expression of molecular markers. These subtypes are believed to arise from distinct epithelial cell populations within the mammary gland. Uncovering the molecular mechanisms governing epithelial cells in the mammary gland is vital for the discovery of new targeted therapeutics. Regulation of alternative splicing underpins many developmental processes and is often utilised in cancer to promote oncogene expression and down regulate tumour suppressor genes. We have undertaken a comprehensive analysis of alternative splicing in the three distinct epithelial cells in the mammary gland, basal cells (mammary stem cell enriched), luminal progenitors and mature luminal cells. These data indicate that the mammary gland displays excessive intron retention compared to other murine organs. This intronic retention increases with the epithelial cell differentiation state. Intron retention within a transcript most often leads to nonsense-mediated decay, but there appears to be very little association between retention and gene expression, suggesting a complex level of gene regulation occurs within the mammary gland. Breast cancer is the only known tumour type where intron retention is higher in normal cells compared to neoplastic cells. We are currently investigating the role of intron retention during the tumourigenesis process through the use of murine mouse models of Basal-like pre-neoplasia. Basal-like tumours remain difficult to treat given the lack of targeted therapeutics. We aim to uncover critical splicing factors important for basal-like tumour transformation that may provide novel drug targets.