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Title: Expression and role of protein kinase C isoforms in tamoxifen resistant breast cancer
Author: Lewis, Ian
ISNI:       0000 0004 2748 1932
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2005
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The development of resistance to anti-oestrogenic therapies such as tamoxifen is a serious clinical problem in the treatment of breast cancer. A specific model of Tamoxifen resistance has been developed in the Tenovus laboratories by maintaining MCF-7 breast cancer cells in Tamoxifen (10" M) for 4-6 months. The resistant cells that arise from these cultures are termed TAM-R cells. We wished to utilize these cells to test the hypothesis that resistance to tamoxifen is due to changes in protein kinase C (PKC) isoform expression. Initially we investigated PKC expression in the TAM-R cells and demonstrated that they express significantly more basal and activated protein kinase C (PKC)-a and 8 than wild type MCF-7 cells. To test the implications of this observation, we wished to specifically and selectively ablate these PKCs in the TAM-R cells and assess the outcomes. The limitations of pharmacological inhibitors such as bisindolylmaleimide LX (Ro31-8220) and Rottlerin were highlighted by our studies which concurs with a general discontent in the current literature over their specificity and efficacy. We therefore utilised RNAi and adenovirus mediated molecular technologies to modulate the PKC-ct and PKC-8 isoform expression profile in the MCF-7 and TAM-R cell lines. Using both RNAi and adenoviral infection of dominant negative mutants we demonstrated that down regulation of PKC-a and PKC-8 blocks both growth factor and oestradiol induced growth in MCF-7 and TAM-R cells. Thus PKC-a and 8 must play an important role in the mitotic pathways utilised by tamoxifen resistant breast cancer cells. Moreover overexpressing PKC-a and 8 in MCF-7 cells allowed them to acquire resistance to tamoxifen and possibly even led to tamoxifen becoming agonistic for these cells, suggesting a role for these isoforms of PKC in inducing the tamoxifen resistant phenotype.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available