Poster Presentation 25th Lorne Cancer Conference 2013

Identification and functional characterisation of miRNAs in breast development and malignancy (#310)

Yuwei Phua 1 , Akira Nguyen 1 , Dan Roden 1 , Warren Kaplan 1 , Hosein Kuoros-Mehr 2 , Alexander Swarbrick 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Genentech , South San Francisco , California, USA

Developmental pathways are often inappropriately activated during tumorigenesis. microRNAs are potent regulators of gene expression during development and are implicated in regulating tumourigenesis and metastasis. Our aim is to identify microRNAs controlling breast cancer phenotype. The terminal end buds (TEBs) of the developing mammary gland in pubertal mice exhibit certain hallmarks of cancer; they are highly proliferative, invasive, poorly differentiated and possess a stem/progenitor cell population. We have determined the repertoire of microRNA expressed by TEBs and differentiated ducts micro-dissected from pubertal mice. We have identified and validated a number of microRNAs that are differentially expressed in the TEBs and the mature ducts, many of which have unknown roles in mammary development. Amongst the list of candidate microRNAs identified, classic oncogenic microRNAs such as the miR 17-92 cluster, which promote proliferation and invasion, was significantly enriched in the TEBs. miR-31 and miR-184 were the most enriched miRNAs in the TEBs and ducts respectively. We decided to investigate the functional role of miR-184 since it has not been previously characterised in breast cancer. In primary triple negative breast tumours, miR-184 expression was lost when compared to matched normal, due to the epigenetic silencing of the miR184 locus. Ectopic overexpression of miR-184 in breast cancer cells reduced proliferation and self-renewal in vitro. Most importantly, miR-184 overexpression suppresses tumour formation and prolongs survival in vivo. Gene expression profiling coupled with data integration demonstrate that miR-184 represses multiple members of the AKT/mTOR signaling pathway suppressing protein synthesis. In summary, we have used a mammary developmental model as a novel and powerful tool in identifying well-characterised and novel microRNAs whose roles in mammary gland development and cancer pathogenesis warrant further investigation.