Molecular Mechanism of Efficient Treatment of Resistant Breast Cancer Using a Mitochondria-Targeting Compound
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Cancer is one of the prevailing causes of death worldwide. The prognosis of this hard-to- treat disease is poor and may be attributed to high rates of mutations leading to heterogeneity of tumours, and thus requiring an invariant target to selectively combat malignant cells. Her2high breast carcinomas occur in up to 30% of breast cancer patients and remain to be one of the hardest-to-treat breast cancers. The central dogma of Her2 localised at the plasmatic membrane has allowed for the development of commercially available antibody-based therapies epitomised by Herceptin™. However, Herceptin™ is not always efficient, causing re-lapse and even worse prognosis. Tamoxifen, a hormone- based agent, is a frequently used drug for estrogen-positive breast cancer patients, targeting mitochondria at supra-pharmacological doses. Thus, this study focuses on a novel therapeutic approach to combat resistant cancers such as Her2high breast cancers. Intriguingly, we observed, along with only one other study, that Her2 is also present in mitochondria of Her2high cells and tumours, probably altering their bioenergetic metabolism. We also show that Her2high cells exhibit higher mitochondrial membrane potential, and exhibit higher respiration through oxidative phosphorylation compared to Her2low cells. Further investigations of these cells show increased levels of complex I of the ETC, as well as the respirasome. However, the mechanism of Her2 translocation to mitochondria is not understood. Our findings led us to anticipate that targeting mitochondria could be an effective mode of therapy especially, but not limited to, resistant Her2high breast carcinomas. Due to this notion, we synthesised a mitochondrially targeted anti-cancer agent acting via the mitochondrial ETC, and evaluated the mechanism of its efficacy towards Her2high cells. The new compound that is the focus of this project is mitochondrial targeted tamoxifen (MitoTAM).
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
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In order to comply with copyright the following have not been published here: Table 1 page 29 Table 2 Page 32 Figure 1 Page 42 Figure 2 Page 45 Figure 3 paqge 50 Figure 4 page 59 Table 3 page 60
Her2high breast carcinomas
Mitochondrial targeted tamoxifen (MitoTAM).