There is accumulating evidence that primary breast cancers display phenotypic and functional heterogeneity and that only a minority of cells (tumour propagating cells, TPCs) in a breast tumour are capable of tumour initiation, metastatic dissemination and growth. Identifying factors that regulate the properties of TPCs and how they limit metastatic growth is therefore important for developing strategies to treat patients with metastatic tumours. The Inhibitor of Differentiation 1 (Id1) is a helix-loop-helix protein which functions as a transcriptional regulator. Id1 is highly expressed in metaplastic breast cancers and is required for metastasis in experimental models. However, the mechanism by which Id1 mediates metastasis in breast cancer remains largely unknown.
Our work aims to define the mechanism of Id1 function and investigate whether Id1 and its associated pathways are potential therapeutic targets for the triple-negative breast cancers (TNBC). Examination of ID1 expression profiles in a cohort of breast cancer patients showed that ID1 expression is associated with the TN and HER2-enriched subtypes of breast cancer. Furthermore, ID1 expression is enriched in clinically obtained brain metastases compared to patient matched primary breast cancers. Tumour cells endogenously expressing Id1 were isolated from two different syngeneic mouse models of breast cancer- an Id1-GFP knock-in C3-SV40 Large T transgenic mouse model and a syngeneic p53 null mouse mammary gland tumour model. Phenotypic characterisation demonstrated that the Id1 positive cells are enriched for tumour initiating, self-renewal and metastasis forming potential both in vitro and in vivo. Functional knock down studies using inducible RNAi in the metastatic 4T1 model demonstrated that Id1 is required for tumour propagating functions, both in the context of cell proliferation and self-renewal in vitro, as well as primary tumour growth and during metastatic colonization of the lung in animal models. Transcript profiling and RNA-Seq experiments revealed several novel Id1 target genes and suggested a regulation of Id1 function by Bmi1/Mel18 and TGF-β signaling pathway. Current directions include defining the transcriptional and proteomic (binding partners) landscape of the rare cells, which are critical for tumorigenesis and metastasis in the TNBC subtype.