Endocrine Abstracts (2002) 3 P133

Alterations in expression levels of ER subtypes and their coregulators in endocrine resistant breast cancer

AT Parkes, F Ponchel, S Burdall, S Farmery & V Speirs

University of Leeds, Leeds, UK.

Hormone dependent breast cancer is preferentially treated with Tamoxifen (TAM), an Estrogen Receptor antagonist. Although the initial response to TAM is tumour regression the majority of patients eventually relapse. Understanding the mechanisms that contribute to this resistant phenotype may influence the success of patient response to TAM and prevention of recurrence.

A role for ER coactivator and corepressor proteins has been suggested to contribute to TAM resistance. The aim of this study was to identify any changes in ER coregulatory proteins in association with ER-alpha, ER-beta, and ER-beta cX. A TAM-resistant cell line model was developed by the continued culture of TAM-sensitive MCF-7 breast cancer cells in the presence of 4OH-TAM. Cell response to TAM was periodically assessed by MTT assay. Real-Time PCR analysis was used to quantify ER-alpha,ER-beta,ER-beta cX, and the coregulatory factors AIB-1, SRC-1, SRA, NCoR, SMRT and REA from cell extracts. Our results demonstrate down-regulation of all 3 ER subtypes as resistance develops. An increase in levels of the coactivators AIB-1, SRC-1, SRA, and the corepressor REA have also been shown, whilst steady state levels of NCoR and SMRT were observed. Altered levels of ER coregulators involved in the ER signalling pathway may influence the rate at which TAM-treated breast cancer progresses from a compliant to a resistant state, highlighting potential targets for interaction in this transition.

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