The oestrogen receptor (ER) is a nuclear steroid receptor that upon activation by its ligands (e.g. oestrogen) initiates a cascade of events resulting in increased cellular proliferation in its target tissues (Warner et al, 1999). Since oestrogen is one of the most potent mitogens for breast cancer cells, it is no surprise that ER is the most important target for endocrine therapy of breast cancer (Osborne, 1998). Recently, a number of factors which regulate nuclear hormone receptor activity have been identified. Cofactors capable of increasing receptor action, termed coactivators, include transcriptional intermediary factor 1 (TIF1), nuclear receptor interacting protein (NRIP1), nuclear receptor coactivator 2 (TIF2), steroid receptor coactivator 1 (SRC1), amplified in breast cancer 1 (AIB1), the cyclic AMP (cAMP)-response element binding protein (CREB) binding protein (CBP) (Glass et al, 1997;Shibata et al, 1997) and many more. The family of corepressors (negative regulators) of ER is smaller; the best characterized ones being the nuclear receptor corepressor (N-CoR) (Horlein et al, 1995;Shibata et al, 1997) the silencing mediator of retinoid and thyroid receptors (SMRT) (Chen and Evans, 1995;Sande and Privalsky, 1996) and the repressor of ER activity (REA) (Montano et al, 1999). The overexpression of coactivators or the loss of corepressors could lead to deregulation of oestrogen-dependent pathways related to mammary epithelial cell proliferation, and thus to breast tumorigenesis. And indeed, some of the ER cofactors have recently been characterized as playing major roles in breast tumorigenesis (Horlein et al, 1995;Anzick et al, 1997;Shibata et al, 1997). The ER coactivator AIB1 was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number are elevated in human breast cancer, and subsequent analysis in 105 breast tumour specimens confirmed its overexpression (Anzick et al, 1997). Interestingly, the breast/ovarian tumour suppressor gene BRCA1 has recently been characterized as an ER corepressor (Fan, 1999) again suggesting that ER coregulators are crucial in breast tumorigenesis. Thus, it might be expected that other ER coactivators and corepressors might play similar important roles in breast cancer development and progression.The nuclear matrix protein SAFB (Renz, 1996;Oesterreich, 1997) has been shown to be an ER corepressor . ER and SAFB interact in in-vitro binding assays (Glutathione-S-Transferase [GST]-pulldown assays) and in cell lines (co-immunoprecipitation experiments). In cell lines, there is binding of SAFB to ER in the presence or absence of oestradiol; however, binding is significantly increased by the antioestrogen tamoxifen. Overexpression of SAFB results in repression of oestrogen-mediated transactivation of gene expression by the ER. Furthermore, as a result of SAFB overexpression, the antagonist activity of tamoxifen on ER can be enhanced, and the agonist activity of tamoxifen can be inhibited.These results led us to investigate whether the ER corep...