Resistance to Tamoxifen with Persisting Sensitivity to Estrogen: Possible Mediation by Excessive Antiestrogen Binding Site Activity

The growth of a large proportion of estrogen receptor-positive breasttumors is stimulated by estrogen and can often be controlled throughantiestrogen therapy. Resistance to antiestrogen (AE) therapy can occurâ»huetumors retain the expression of estrogen receptors (ERc) andremain functionally responsive to estrogens. The ability of specific antiestrogen binding sites (AEBS) to prevent AE from interacting withERc has been examined as a possible mechanism through which thisappropriation of AE could interfere with antiestrogen action. Comparisons were performed between uterine preparations where ERc activityexceeded AEBS binding and liver preparations where AEBS bindingpredominated. Identical estimates of ERc activity were obtained in uterine preparations using either |'H]estradiol or | '111-4(<II-tâ¡imoiU-nandradioinert diethylstilbestrol (a,o'-diethyl-4,4'-stilbenediol) to estimatenonspecific binding. AEBS binding was observed only when ['IIj-IOI Itamoxifenwas used, while binding to Type II sites was resolved onlywith |'II|estradiol. When excess AEBS activity predominated, analyseswith radiolabeled estrogen and antiestrogen present simultaneouslyshowed that virtually all of the antagonist was bound to AEBS with littleof the antagonist available to associate with ERc. In an effort to relatethese observations to AE resistance per se, ERc and AEBS were measured in MCF-7 human breast cancer cells (ERc-positive, responsive toestrogens and antiestrogens) and in variant AE-insensitive LV-2 humanbreast cancer cells (ERc-positive, responsive only to estrogens). In I -resistant LV-2 cells, the ratio of AEBS:ERc was approximately threetimes greater than in MCF-7 cells. Examination of 128 human breastcarcinomas revealed that AEBS activity was present and could exceedERc activity. Importantly, the partition of significant AE away fromERc was observed in human specimens. These observations identify abiochemical mechanism for antiestrogen resistance through which AEaccess to ERc can be totally incapacitated while sensitivity to estrogenscontinues. These observations indicate that AEBS activity, in additionto ERc activity, may provide helpful information for predicting theresponse of certain cancers to hormonal therapy.