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Novel strategy to inhibit the oncogenic transcription factor c-Myc in triple-negative breast cancer

Mejzini, Rita (2016) Novel strategy to inhibit the oncogenic transcription factor c-Myc in triple-negative breast cancer. Honours thesis, Murdoch University.

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Triple-negative breast cancer (TNBC), characterised by the minimal expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2), is an aggressive clinical phenotype. Its expression profile means it is not amenable to hormone therapy or HER-2 directed treatments with systemic treatment options limited to cytotoxic chemotherapy. There is therefore an unmet need for new targeted treatments for this cancer subtype. Transcription factor c-Myc (Myc) is frequently deregulated in these cases and is implicated in breast cancer development and progression. Omomyc is a peptide able to interfere with the protein-protein interactions of Myc, inhibiting transcriptional activation of its target genes. Here I report on the use of a new cell penetrating peptide (CPP), 1746, to deliver Omomyc to TNBC cells and on a truncated version of the Omomyc peptide (Omi) linked to 1746 (1746-Omi) and the traditional CPP Penetratin (Penetratin-Omi). I found 1746-Omomyc reduced the viability of TNBC cells overexpressing Myc by reducing proliferation. The truncated peptides were not as potent but demonstrated greater selectivity towards cancer cells. Penetratin-Omi had a greater activity than 1746-Omi and reduced cell viability primarily through cell death rather than reduced proliferation. The effect of 1746-Omomyc and Penetratin-Omi on the regulation of selected downstream Myc targets was determined by qRT-PCR and was consistent with but does not confirm Myc inhibition. This demonstrates the potential of 1746-Omomyc as an effective Myc inhibitor in TNBC. The shortening of Omomyc’s sequence reduced the peptides activity with much higher concentrations of 1746-Omi and Penetratin-Omi required to effect cancer cell viability. The mechanism of action of Penetratin-Omi also differed from 1746-Omomyc, indicating the possibility of a cargo-dependent cytotoxicity at high concentrations. Improving the design of the peptides could increase efficiency and reduce the possibility of any cytotoxic side effects.

Item Type: Thesis (Honours)
Murdoch Affiliation: School of Veterinary and Life Sciences
Supervisor(s): Blancafort, Pilar
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