Endocrine Abstracts (2004) 7 P116

Novel actions of the anti-estrogen faslodex at the estrogen receptor

FJ Fleming1,2, AD Hill1,2, EW McDermott1,2, NJ O'Higgins1,2 & LS Young1,2

1Department of Surgery, Saint Vincent's University Hospital, University College Dublin, Ireland; 2Conway Institute of Biomolecular Biomedical Research, University College, Dublin, Ireland.

Introduction: Faslodex (Fulvestrant) is a novel antiestrogen, which has been demonstrated to have clinical efficacy in metastatic breast cancer. It is thought to mediate it's effects by downregulating ER expression. ER-alpha and ER-beta function as transcription factors to modulate genes relevant to breast cancer progression. Both interact with nuclear regulatory proteins to enhance or inhibit transcription. We hypothesized that Faslodex may modulate the recruitment and interaction of co-regulators with ER which could account for it's pure antagonist profile at the ER.

Methods: The ability of beta-estradiol and Faslodex (ICI 182,780) to modulate the protein expression of ER, the co-activator SRC-1, and the co-repressor SMRT in primary breast cancer cell cultures and cell lines was assessed by western blotting. The interaction of the ER with the estrogen response element (ERE) in the presence of beta-estradiol and ICI 182,780 was assessed by electromobility shift assays (EMSA). ER-co-regulator interactions were assessed by immunoprecipitation.

Results: beta-estradiol induced an up-regulation in ER-beta and co-regulator protein expression as determined by immunoblotting and increased ER-alpha/ER-beta interaction with the ERE as assessed by EMSA. ICI 182,780 decreased ER-alpha, ER-beta and SRC-1 expression. SMRT, but not SRC-1 was recruited to the ERE in the presence of ICI 182,780. Both ER-alpha and ER-beta preferentially bound SRC-1 in the presence of beta-estradiol. Conversely, in cells treated with ICI 182,780 ER-alpha and ER-beta bound SMRT and inhibited ER-SRC-1 interactions.

Conclusions: Recruitment of the co-repressor SMRT to the ERE and increased ER-SMRT interaction may be central to Faslodex's profile as a novel anti-estrogen.

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