MicroRNA profiling of the developing mammary gland identifies miR-184 as a candidate breast tumour suppressor gene (Affymetrix)

The study of mammalian development has offered many insights into the molecular aetiology of cancer. We previously used analysis of mammary morphogenesis to discover a critical role for GATA-3 in mammary developmental and carcinogenesis. In recent years an important role for MicroRNAs (miRNAs) in a myriad of cellular processes in development and in oncogenesis has emerged. In this study, microRNA profiling of stromal and epithelial cellular subsets microdissected from the developing mouse mammary gland revealed many microRNAs with expression restricted to various cellular subsets. MicroRNA-184 (miR-184) was exclusively expressed in epithelial cells and markedly upregulated during differentiation of the proliferative, invasive cells of the pubertal terminal end bud (TEB) into ductal epithelial cells in vivo and in FACS-sorted mammary stem cells (MaSCs) versus luminal epithelial cells. miR-184 expression was silenced in mouse tumour models compared to non-transformed epithelium and in a majority of breast cancer cell line models. Ectopic reactivation of miR-184 inhibited the proliferation and self-renewal of metastatic triple negative breast cancer (TNBC) cell lines in vitro and delayed tumour formation and reduced metastasis in vivo. Gene expression studies uncovered multi-factorial direct regulation of genes in the AKT/mTORC1 pathway by miR-184. In clinical breast cancer tissues, expression of miR-184 is lost in primary TNBCs while the miR-184 promoter is methylated in a subset of lymph node metastases from TNBC patients. These studies elucidated a new layer of regulation in the PI3K/AKT/mTOR pathway with relevance to mammary development and tumour proliferation and metastasis.

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Phua YW, Nguyen A, Roden DL, Elsworth B, Deng N, Nikolic I, Yang J, Mcfarland A, Russell R, Kaplan W, Cowley MJ, Nair R, Zotenko E, O'Toole S, Tan SX, James DE, Clark SJ, Kouros-Mehr H, Swarbrick A