Clinical impact of assay of estrogen receptorβcx in breast cancer

Since 1996 when estrogen receptor β (ERβ) was discovered, much effort has been devoted to the question of the value of ERβ as a prognostic and/or predictive factor in breast cancer and its potential as a novel target for pharmacological intervention. When estrogen receptors are applied on sucrose gradients and quantified by ligand binding, we found that in contrast to ERα, which has a narrow tissue distribution, ERβ is expressed in many tissues including both normal and malignant breast tissue. Receptor protein levels in tissues can also be measured from the intensities of bands after Western blotting and can be quantified when purified and quantified receptor is used as a standard. With this technique, we found that there were some tumors which had over 600 fmol/mg of ERβ protein but no detectable estradiol binding. In such tumors, RT-PCR analysis revealed that ERβcx is the only ERB isoform present. ERβcx is a splice variant which utilizes an alternative exon 8. This change in the C-terminus results in very poor binding to estradiol (E2) and has a dominant negative effect on ERa function. Imunohistochemical analysis with an ERflcx specific antibody in 115 ERα-positive breast cancers revealed that about half of the samples expressed ERβcx protein. Initial analysis of samples from patients with preoperative tamoxifen treatment revealed that ERα-positive tumors expressing ERβcx and lacking PR seemed to be resistant to the antiestrogen. We conclude that, in order to better characterize breast cancers and design appropriate therapy for individual patients, assays for ERβcx must be made available to clinicians.