Poster Presentation 25th Lorne Cancer Conference 2013

A critical role for ID4 in mammary stem cells and triple negative breast cancer (#223)

Simon Junankar 1 , Sandra O'Toole 1 2 3 , Radhika Nair 1 , Andrea McFarland 1 , Kyuson Yun 4 , Robert Sutherland 1 , Alexander Swarbrick 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  3. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, NSW, Australia
  4. The Jackson Laboratory, Bar Harbor, Maine, USA

Breast cancer is a heterogeneous disease that can be divided into a number of subtypes with distinct molecular characteristics, aetiology and clinical outcome. Understanding the molecular drivers of these subtypes allows for improved patient care. It is now clear that pathways that regulate normal mammary development become disregulated in cancer and can become drivers of tumour progression, and an understanding of these pathways, for example the role of the oestrogen receptor (ER) as a target for tamoxifen has improved treatment for ER positive breast cancer patients. However there are no clinically approved targeted treatments for triple-negative breast cancers. Furthermore the pathways that drive triple-negative breast cancer are poorly understood.  By studying key genes involved in mammary development we aim to identify novel targets for breast cancer treatment. We now show that the transcriptional regulator Inhibitor of DNA binding 4 (ID4) is expressed exclusively in the stem and myoepithelial cell populations of the murine mammary gland and that mammary stem cells can be prospectively identified and isolated by their high expression of Id4. Loss of Id4 in the mammary gland leads to a defect in mammary gland development and a reduction in stem cell number. Furthermore enforced overexpression of Id4 in a normal mammary epithelial cell line inhibited luminal differentiation in vitro and increased tumour formation in vivo. Id4 overexpression is also associated with down regulation of transcription factors that promote luminal differentiation. 50% of triple-negative breast tumours highly express ID4, which strongly associated with good patient outcome and reduced lymph node metastasis. We propose that the role of ID4 in maintaining the stem cell pool through inhibition of luminal differentiation is maintained in a proportion of triple-negative breast cancers and by further understanding the mechanism of ID4 action we aim to identify novel therapeutic targets.