Loddo, M;
(2015)
Dysregulation of the cell cycle in breast cancer.
Doctoral thesis , UCL (University College London).
Abstract
Dysregulation of the cell cycle underlies the uncontrolled cell proliferation that characterises cancer. The cell cycle machinery can be regarded as a final and critical step in growth control downstream of complex and redundant oncogenic signalling networks and therefore a potentially attractive intervention point for cancer diagnostics and therapeutics. In the work of this thesis I investigated dysregulation of the cell cycle engine in breast cancer aimed at identification of new prognosticators and therapeutic targets. I conducted an analysis of the DNA replication machinery (G1/S regulators) and the mitotic engine proteins (G2/M regulators) in a cohort of invasive breast cancers. I was able to demonstrate that these critical regulators of the cell division cycle, namely Mcm2, geminin, Aurora A, Plk1 and H3S10ph are powerful independent prognosticators of disease progression. Notably multiparameter analysis of these core G1/S and G2/M regulators revealed that breast cancer resides in three distinct cell cycle states and that these phenotypes impact on prognosis and also predict response to S- and M-phase directed chemotherapies. This cell cycle analysis also revealed a profound mitotic perturbation in breast cancer, namely a prophase/prometaphase delay. This tumour specific mitotic phenotype was compared with the mitotic phenotypes generated in the MitoCheck screen (www.mitocheck.org), a genomewide RNAi screen performed in HeLa cells, aimed at the identification of genes involved in the process of cell division. This led to the identification of pregnancy associated plasma protein A (PAPPA) gene as a new candidate tumour suppressor in breast cancer. Intriguingly I was able to show that PAPPA functions as an evolutionary conserved regulator of mitosis in mammalian cells, is epigenetically silenced in early multi step breast tumourigenesis, and has potential as a prognosticator in mammography detected disease.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Dysregulation of the cell cycle in breast cancer |
| Event: | UCL (University College London) |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1472740 |
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