Elevated Src kinase activity accompanies endocrine-resistance in breast cancer and promotes an aggressive cell phenotype

Morgan, Liam David ORCID: https://orcid.org/0000-0002-7571-6025 2007. Elevated Src kinase activity accompanies endocrine-resistance in breast cancer and promotes an aggressive cell phenotype. PhD Thesis, Cardiff University.

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Abstract

Despite the effectiveness of tamoxifen in the treatment of oestrogen-receptor-positive breast cancer, a significant proportion of initially-responsive tumours will develop resistance. Using an in vitro cell-model (Tam-R), our laboratory has previously demonstrated that altered growth-factor signalling contributes to tamoxifen-resistant growth. Furthermore, preliminary studies have revealed that acquired tamoxifen-resistance is also accompanied by an aggressive cell-phenotype. Src plays a key role in the regulation of cellular events such as proliferation, migration and invasion. Given that Src has been implicated in tumour progression and metastasis, the aims of this thesis were to further investigate the aggressive phenotype of tamoxifen-resistant breast cancer cells, together with the role of Src in such behaviour. Characterisation of Tam-R cells revealed that these cells grew in loosely-packed colonies and displayed a more angular appearance, which is characteristic of cells undergoing an EMT-like process. Furthermore, Tam-R cells demonstrated increased growth and a significantly augmented motile and invasive phenotype compared to MCF7wt. Analysis of Src expression in these cell-lines revealed no change in mRNA or protein levels however, a dramatic increase in basal Src activation (phosphorylation at Y419) was observed in Tam-R cells. Inhibition of Src in Tam-R cells using AZM555130 restored cell-cell contacts, decreased cell-matrix attachment and suppressed migration and invasion in a dose-dependent manner. Furthermore, inhibition of Src was accompanied by decreased proliferation and a corresponding reduction in EGFR signalling. Conversely, over-expression of constitutively-active Src in MCF7wt cells resulted in elevated growth-factor signalling and FAK/paxillin activity, and promoted increased cell growth, migration and invasion. Importantly, these cells demonstrated insensitivity to the growth-inhibitory effects of tamoxifen, an effect reversed by co-treatment with AZM555130. Together, these data suggest that Src plays a pivotal role in mediating the aggressive phenotype of tamoxifen-resistant breast cancer cells in vitro, and that targeting Src in such cancers may be of therapeutic advantage.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
ISBN:	9781303182143
Funders:	Tenovus, Welsh School of Pharmacy, Cardiff University
Date of First Compliant Deposit:	30 March 2016
Last Modified:	25 Oct 2022 08:50
URI:	https://orca.cardiff.ac.uk/id/eprint/55686

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