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dc.contributor.supervisor Gibson, Spencer (Biochemistry & Medical Genetics) en
dc.contributor.author Booy, Evan Paul
dc.date.accessioned 2011-01-10T16:46:29Z
dc.date.available 2011-01-10T16:46:29Z
dc.date.issued 2011-01-10T16:46:29Z
dc.identifier.uri http://hdl.handle.net/1993/4334
dc.description.abstract Myeloid Cell Leukemia-1 (Mcl-1) is a widely expressed anti-apoptotic member of the Bcl-2 family that is elevated in a variety of tumour types including breast cancer. Mcl-1 promotes tumour cell survival and drug resistance and was a mechanism of resistance to first generation Bcl-2 family inhibitors. To determine the significance of Mcl-1 in breast cancer, we evaluated the regulation of Mcl-1 by signalling via the epidermal growth factor receptors (EGFRs). EGFR signalling is frequently deregulated in breast cancer and leads to increased proliferation and survival of tumour cells. We aimed to determine whether Mcl-1 is a critical downstream effector of this pathway and therefore an important therapeutic target. We found that Mcl-1 protein and messenger RNA levels were rapidly induced upon stimulation of breast cancer cells with epidermal growth factor. This induction was blocked by inhibitors of the Ras/Raf/Mek/Erk signalling cascade and was dependent upon activation of the transcription factor Elk-1. We found Mcl-1 to be an essential survival protein, as targeted knock-down with small interfering RNA alone was sufficient to induce apoptosis. Mcl-1 may be critical for the survival advantage conferred by EGFR activation, as prevention of its up-regulation by Mek/Erk inhibitors significantly reduced the drug resistance conferred by EGF. Furthermore, we found a correlation between phosphorylated Elk-1 and Mcl-1 protein levels in breast tumour samples. Therefore, we conclude that Mcl-1 is an important downstream effector of survival and drug resistance mediated by elevated EGF signalling, making it an important therapeutic target in breast cancer. en
dc.format.extent 12348279 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Mcl-1 en
dc.subject breast cancer en
dc.subject Elk-1 en
dc.subject EGF en
dc.subject ErbB1 en
dc.subject ErbB2 en
dc.subject ErbB3 en
dc.title Mcl-1 in breast cancer: regulation by the EGF receptor family and role in cell survival and drug resistance en
dc.degree.discipline Biochemistry and Medical Genetics en
dc.contributor.examiningcommittee Murphy, Leigh (Biochemistry & Medical Genetics) Mowat, Michael (Biochemistry & Medical Genetics) Shiu, Robter (Physiology) en
dc.degree.level Doctor of Philosophy (Ph.D.) en
dc.description.note February 2011 en


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