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Title: Modification of oestrogen signalling during the acquisition of hormone resistance in breast cancer cells
Author: Kuske, Barbara I.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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Breast cancer cell lines were selected that encompassed the range of oestrogen and anti-oestrogen sensitivities from the E2-dependent and tamoxifen-sensitive MCF-7 cell line through the less sensitive LCC-1 and LCC-2 lines to the insensitive LCC-9 and independently derived LY2 line. All lines had been derived from MCF-7 cells. These models represent different endocrine phenotypes and were designed to reflect sequential changes in the clinical progression from hormone sensitive to hormone insensitive and antioestrogen resistance. All resistant lines possess greater levels of ERα mRNA than wild-type MCF-7 cells. E2 downregulated ERα mRNA and protein. Results suggest ERα functionality in all of the cell lines. Analysis of mRNA levels of several ER target genes (pS2, progesterone receptor (PR), cathepsin D and MYC) indicated informative differences between lines. pS2 was highly expressed in resistant lines as was PR in most lines compared to MCF-7 cells. E2 and tamoxifen produced attenuated or no effects in pS2 expression compared to the marked induction produced by E2 in MCF-7 cells. Minor changes were also observed in the expression levels of various coactivators (SRC-1, SRC-2, SRC-3) and corepressors (NCoR, SMRT and RIP140) investigated by qRT-PCR and Western blot. A subset of three cell lines (MCF-7, LCC-1 and LCC-9) was used to examine transcription complex assembly at the pS2 promoter in response to E2 utilizing chromatin immunoprecipitation. This identified a dynamic cycle of increasing H4 acetylation (indicative of active transcription) and ERα as well as cofactor recruitment upon E2 addition in MCF-7 cells. A distinctive GH4 acetylation pattern was revealed for LCC-1 and LCC-9 cells. While ERα recruitment was similar to MCF-7 cells, particularly strong SRC-1 and SRC-3 recruitment was detected in LCC-1 but most markedly in LCC-9 cells, implying altered pS2 transcription complex assembly.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available