Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Identification & characterisation of EMT-regulatory miRNAs in mammary development and carcinogenesis (#116)

Akira Nguyen 1 , Yuwei Phua 1 2 , Hosein Kouros-Mehr 3 , Alexander Swarbrick 1 2
  1. Cancer Research Program, Garvan Institute of Medical Research, Sydney, N.S.W., Australia
  2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, N.S.W., Australia
  3. Tumour Biology and Angiogenesis Department, Genentech, Inc., South San Francisco, California, United States of America

Metastasis is the major underlying cause of breast-cancer deaths and at present is incurable. The molecular pathways which endow cancer cells with the ability to disseminate from the primary tumour, invade through stroma, and re-establish themselves in distal tissues are not well understood. At the cellular level, self-renewal, migration and invasion are recognised as key cellular processes driving the metastatic phenotype. During the epithelial-to-mesenchymal transition (EMT), epithelial cells lose polarity and gain mesenchymal traits, including the capacity to migrate and self-renew. As such, re-activation of the EMT programme in tumours is believed to be a major component of metastatic progression.
We utilised an innovative ex-vivo microarray technique to identify miRNAs that distinguish epithelial cells from mesenchymal cells in the developing mammary gland, and hence may regulate EMT in the breast. Comparison of the miRNA expression profiles of epithelium and stroma revealed an epithelium-specific expression pattern for miR-183 and miR-200c; both miRNAs have previously been implicated in the regulation of EMT-associated self-renewal and invasion. Significantly, as we have identified these miRNAs in the physiologically relevant milieu of the mammary gland, they likely represent pathways of EMT regulation native to the breast. Consistent with a role in EMT regulation, we found that miR-183 and miR-200c expression is lost in triple negative patient samples, compared to matched normal tissue.
As miR-200c function is already well characterised, our efforts are currently focused on investigating the potential role of miR-183 in regulation of EMT in mammary epithelium. We have generated normal mammary epithelial and breast cancer cell lines with doxycycline-inducible expression of miR-183 which have enabled us to investigate the effect of miR-183 in in vitro models of EMT and metastasis, and also in vivo using pre-clinical mouse models of breast cancer.