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The exploration of CD44 as a mediator of a drug resistant phenotype in ER+ breast cancer

Bellerby, Rebecca 2015. The exploration of CD44 as a mediator of a drug resistant phenotype in ER+ breast cancer. PhD Thesis, Cardiff University.
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The majority of breast cancers express the oestrogen receptor and are potentially amenable to endocrine therapy, however the clinical effectiveness of these agents is limited by the phenomenon of acquired resistance which is associated with disease relapse and poor prognosis. It has been previously demonstrated that the CD44 receptor is overexpressed in acquired tamoxifen resistance where it associates with an enhanced migratory phenotype, however little is known regarding the effects of CD44 splice variants in this context. This thesis aimed to explore the role of CD44 variant isoforms in a model of ER+ breast cancer derived tamoxifen-resistance (Tam-R cells) and expand these explorations into an additional model of acquired fulvestrant-resistance (Fas-R cells). Multiple CD44 isoforms were found to be upregulated in resistance although a differential expression profile was observed between Tam-R and Fas-R cells. Inhibition of global CD44 expression in both endocrine resistant models led to a loss in their migratory, proliferative and invasive capacity and attenuated their responses to the CD44 ligand, hyaluronan. Overexpression of CD44v6 in endocrine sensitive MCF-7 cells induced EGFR pathway activation leading to enhanced cellular invasion, and attenuated response to fulvestrant. Accordingly, CD44v6 suppression in Tam-R cells resulted in a loss of EGFR pathway signalling and reduced invasion. Preliminary clinical analysis revealed that co-expression of CD44v6 and EGFR associated with a trend for worsened outcome in ER+ breast cancer patients treated with tamoxifen. These data suggest that upregulation of CD44v6 may contribute to an aggressive phenotype in tamoxifen resistant cells through a mechanism involving the EGFR. Future use of CD44v6 and EGFR as biomarkers may have potential therapeutic value to predict a cohort of ER+ breast cancer patients which relapse earlier on tamoxifen and may thus require more aggressive treatment strategies.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: Q Science > Q Science (General)
Uncontrolled Keywords: CD44, endocrine resistance, breast cancer, migration, invasion, proliferation
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:56

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