Poster Presentation 27th Lorne Cancer Conference 2015

Characterising the molecular function of Inhibitor of Differentiation 4 in poor prognosis basal-like breast cancer (#116)

Laura Baker 1 2 , Simon Junankar 1 , Christoph Krisp 3 4 5 , Aurelien Serandour 6 , Hisham Mohammed 6 , Rosalind Launchbury 6 , Daniel L Roden 1 , Radhika Nair 1 2 , Iva Nikolic 1 2 , Wee Siang Teo 1 2 , Jessica Yang 1 , Andrea McFarland 1 , Sunil Lakhani 7 , Sandra O'Toole 1 2 8 9 , Mark Molloy 3 5 , Jason Carroll 6 , Alexander Swarbrick 1 2
  1. The Kinghorn Cancer Center and Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  3. Australian Proteome Analysis Facility (APAF), Macquarie University, Sydney, NSW, Australia
  4. Department of Analytical Chemistry, Biomolecular Mass Spectrometry, Ruhr-University Bochum, Bochum, Germany
  5. Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia
  6. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom
  7. The University of Queensland, UQ Centre for Clinical Research, School of Medicine and Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
  8. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  9. Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed at an earlier age, with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Poor survival outcome in BLBC is compounded by a lack of targeted treatments. Detailed understanding of the molecular mechanisms underpinning this subtype of breast cancer is essential to the design of better therapeutic options in BLBC. In this study, we show that Inhibitor of Differentiation 4 (ID4), a key transcriptional regulator involved in stem cell homeostasis and normal mammary development, is overexpressed in a subset of BLBCs, identifying patients with poor short-term survival and response to chemotherapy. Through loss of function approaches in vitro and in vivo, we confirm ID4 as a crucial regulator of the poor prognosis phenotype in BLBC.
The molecular mechanisms through which ID4 controls this phenotype are not well characterised. Current models predict ID4 to act in a simplistic dominant-negative manner to directly regulate gene expression by altering transcriptional control. Here we present evidence that ID4 binds to chromatin through novel protein-protein interactions. Using an unbiased cutting-edge technique termed Rapid Immunoprecipitation and Mass Spectrometry of Endogenous proteins (RIME), we comprehensively characterise ID4 protein-protein interactions in BLBC. Furthermore, through chromatin immunoprecipitation and sequencing (ChIP-seq), we demonstrate novel regions of ID4 enrichment in the BLBC genome.
Understanding the molecular mechanism of ID4 function has wider implications for understanding gene regulation in many tissue types, both in a developmental and diseased context. By stratifying patients into good and poor prognosis groups based on ID4 expression, we can delineate the complexity of heterogeneous BLBC and facilitate patient-specific treatment strategies. Additionally, characterisation of unknown downstream signalling pathways and gene regulatory networks, will enable the identification of novel targeted therapeutic options.