MicroRNA-184 (miR-184) represses tumour progression by negatively regulating the AKT/mTORC1 protein synthesis pathway

Download files
Access & Terms of Use
open access
Copyright: Phua, Yuwei
Altmetric
Abstract
Breast cancer patients who suffer from a relapse and develop metastatic disease are currently incurable due a lack of targeted therapies, in particular towards the triple negative subtype, a subset of basal like subtype. MicroRNAs (miRNAs) are now regarded as potent regulators of a myriad of cellular processes in development and in oncogenesis. My Phd thesis looks at identifying miRNAs that are critical in regulating mammary ductal development, cancer progression and metastasis by utilising an ex vivo developmental model, the terminal end buds (TEBs) in pubertal mice. TEBs are poorly differentiated, highly proliferative and invasive, and enriched for stem and progenitor cell activity, which recapitulate certain hallmarks of cancer in a tightly controlled manner. miRNA expression profiling on the TEBs and mature ducts has identified a subset of candidate miRNAs that might be crucial during mammary gland development. miR-184 was the most highly enriched miRNA in the mature ducts. Currently, the role of miR-184 is uncharacterised in mammary gland development and in breast cancer. Further examination of miR-184 shows that it is silenced in a panel of breast cancer cell lines and some mouse tumour models. Functional characterisation of miR-184 in cancer reveals that miR-184 overexpression inhibits proliferation and self-renewal in metastatic basal like breast cancer cells, delays tumour formation and distant metastatic lesions in mice. Gene expression studies reveal that the tumour suppressive functions of miR-184 is possibly mediated by suppressing several members within the AKT/mTORC1 cascade, which inhibits the activation of S6K1, the key modulator of the protein synthesis pathway. Finally, miR-184 was only undetectable in the triple negative breast cancer (TNBC) samples. Epigenetic studies reveal that the miR-184 promoter is often epigenetically silenced in lymph node metastases of TNBC patients, indicating a possible silencing mechanism. In summary, we have utilised a mammary developmental model to identify a novel miRNA that is critical not only in mammary ductal formation but also in breast cancer progression. In addition, we have elucidated another layer of regulation in the PI3K/AKT/mTOR pathway. These findings uncover a potential therapeutic agent that could be used in combination with other inhibitors to treat TNBC.
Persistent link to this record
Link to Publisher Version
Link to Open Access Version
Additional Link
Author(s)
Phua, Yuwei
Supervisor(s)
Swarbrick, Alexander
Creator(s)
Editor(s)
Translator(s)
Curator(s)
Designer(s)
Arranger(s)
Composer(s)
Recordist(s)
Conference Proceedings Editor(s)
Other Contributor(s)
Corporate/Industry Contributor(s)
Publication Year
2013
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
Files
download public version.pdf 2.36 MB Adobe Portable Document Format
Related dataset(s)