Endocrine Abstracts (2002) 3 P134

A role for co-regulators in estrogen receptor function

FJ Fleming, AD Hill, MJ Duffy, EW McDermott, NJ O'Higgins & LS Young

Department of Surgery, UCD, Dublin, Ireland.

The estrogen receptor is encoded by two genes (ER-alpha and ER-beta). Both function as transcription factors to modulate expression of target genes. ER-alpha has been shown to interact with co-regulators to enhance or inhibit transcription in vitro. We hypothesised that the existence of these co-regulators contribute to the differing clinical response of patients to treatment with the anti-estrogen four hydroxytamoxifen (4-HOT). The aim of this project was to localise ER-alpha and ER-beta and the co-regulator SRC-1 within breast tissue and to examine the ability of tamoxifen and beta -estradiol to regulate the expression of ER-alpha and SRC-1. ER-alpha, ER-beta , and SRC-1 were localised within paraffin embedded human breast tissue by immunohistochemistry. ER-alpha and ER-beta were found to be expressed in the nuclei and to a lesser extent the cytoplasm of tumour cells. Strong positive staining for ER-alpha and ER-beta was detected in invasive ductal carcinoma and invasive lobular carcinoma. SRC-1 was found to be expressed to a much lesser extent and was localised to nuclei of tumour cells. The ability of 4-HOT and beta -estradiol to regulate the protein expression of ER-alpha and SRC-1 in the breast tumour cell line MCF-7 was determined using Western Blotting. ER-alpha was expressed within the cytoplasm and to a greater extent the nucleus of MCF-7 cells. Both 4-HOT and beta -estradiol induced an upregulation of nuclear ER-alpha. An apparent translocation of ER-alpha from the cytoplasm to the nucleus was noted in the presence of beta -estradiol. SRC-1 was located within the nuclear fraction of MCF-7 cells and was up regulated in the presence of beta -estradiol. Localisation of the co-regulator SRC-1 within human breast tissue and the regulation of SRC-1 by beta estradiol in the breast tumour cell line MCF-7 is new evidence that co-regulators specifically modulate ER activation by-beta -estradiol and tamoxifen.

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