Date of Award
PhD (Doctor of Philosophy)
Dr Ann Hopkins
Professor Arnold D.K. Hill
Breast cancer is one of the most common worldwide cancers. Most breast cancer deaths are caused when tumour cells disseminate from the primary tumour to form metastases in other organs. Many intrinsic and extrinsic mechanisms are involved in progression to a metastatic phenotype. Thus, the aim of this thesis was to study from complementary perspectives key mechanisms involved in altering cellular homeostasis that could promote tumour progression. The first aim was to establish primary culture models from human breast tumour and non-tumour tissues, and to validate functional differences between the models that could underpin tumour progression. Tumour cultures were found to senesce significantly less than nontumour cultures. More importantly, calculation of a novel proliferation : senescence ratio revealed that a stepwise increase in this ratio correlated with a tumour progression paradigm, from non-tumour through low grade tumours and finally high grade tumours. Since there were signs that primary cultures were enriched in progenitor/stem cells, the second aim was to determine whether an imbalance in progenitor populations could associate with clinicopathological parameters of cancer progression. Putative progenitor populations were identified by flow cytometry as either double negative (DN) or double positive (DP) for the epithelial marker EPCAM and the myoepithelial marker CALLA. An increased DN : DP ratio was observed to positively correlate with poor prognosis tumours, namely those of high grade, ER-negativity or HER2 positivity. Therefore these results suggest for the first time that not only the presence of single progenitor populations but also maintenance of a correct balance between them could affect tissue homeostasis and contribute to tumour progression. However, altered self-renewal ability is not the only driver for tumour progression, but also altered migratory properties of tumour cells via proteins such as the lipid raft-affiliated protein CD44. Thus the third aim of this thesis was to dissect the role of lipid rafts in regulating CD44-mediated cell migration. In the metastatic cell line MDA-MB-231, CD44 was found to interact with its migratory binding partner ezrin only outside lipid rafts; that forced retention of CD44 in rafts abolished these interactions and concomitantly reduced cell migration. These results suggest a novel role for lipid rafts in sequestering CD44 to regulate its participation in breast cancer cell migration. Taken together, results presented in this thesis suggest that many complementary cellular events promote breast tumour progression. Some of the novel mechanisms uncovered may represent future targets for developing more powerful treatments against breast cancer.
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Donatello S. Extrinsic and intrinsic regulation of breast cancer progression - promoting an aggressive phenotype via alterations in cellular populations and subcellular compartments. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2009.