Estrogen receptor variants ERdelta5 and ERdelta7 down-regulate wild-type estrogen receptor activity

The estrogen receptor (ER) plays a key role in mediating the effect of estrogens. It is the primary target for endocrine therapy for many diseases, including breast cancer. The ER contains six domains that are associated with distinct functions; the presence of all six domains is required for ligand-dependent receptor activity. ER variants, reported in breast tumors and other neoplasms, usually lack one or more domains or a part of a domain. Such deletions can have dramatic effects on ER activity, cellular response to hormone, and response to hormonal therapy. We used simple and rapid yeast systems to understand more clearly how ER variants alter the response of wild-type ER (wtER) to estrogen and antiestrogens. We co-expressed ER variant, ERdelta5 or ERdelta7, with wtER in yeast containing an ERE-LacZ reporter. We found that ERdelta5 and ERdelta7 decreased the response of wtER to 1 nM 17beta-estradiol by 41-43 and 24-34%, respectively. Alone, ERdelta5 displayed weak hormone-independent transcriptional activity that was not affected by tamoxifen or ICI 182,780. ERdelta7, in contrast, showed no constitutive activity and no response to ligands. To further understand whether ERdelta5 and ERdelta7 affect wtER activity by forming a variant:wtER heterodimer, we used the yeast two-hybrid system. The protein-protein interaction results showed that ERdelta5 and ERdelta7 could form neither homodimers with themselves nor heterodimers with wtER. This finding suggests that the influence of ERdelta5 and ERdelta7 on wtER is not mediated by suppressing wtER through heterodimerization.