Resistance to Tamoxifen with Persisting Sensitivity to Estrogen: Possible Mediation by Excessive Antiestrogen Binding Site Activity1

The growth of a large proportion of estrogen receptor-positive breast tumors is stimulated by estrogen and can often be controlled through antiestrogen therapy. Resistance to antiestrogen (AE) therapy can occur »huetumors retain the expression of estrogen receptors (ERc) and remain functionally responsive to estrogens. The ability of specific an tiestrogen binding sites (AEBS) to prevent AE from interacting with ERc has been examined as a possible mechanism through which this appropriation of AE could interfere with antiestrogen action. Compar isons were performed between uterine preparations where ERc activity exceeded AEBS binding and liver preparations where AEBS binding predominated. Identical estimates of ERc activity were obtained in uter ine preparations using either |'H]estradiol or | '111-4(>lI-t¡imo\iU-n and radioinert diethylstilbestrol (a,o'-diethyl-4,4'-stilbenediol) to estimate nonspecific binding. AEBS binding was observed only when [ 'IIj-IOI Itamoxifen was used, while binding to Type II sites was resolved only with |'II|estradiol. When excess AEBS activity predominated, analyses with radiolabeled estrogen and antiestrogen present simultaneously showed that virtually all of the antagonist was bound to AEBS with little of the antagonist available to associate with ERc. In an effort to relate these observations to AE resistance per se, ERc and AEBS were mea sured in MCF-7 human breast cancer cells (ERc-positive, responsive to estrogens and antiestrogens) and in variant AE-insensitive LV-2 human breast cancer cells (ERc-positive, responsive only to estrogens). In \ I resistant LV-2 cells, the ratio of AEBS:ERc was approximately three times greater than in MCF-7 cells. Examination of 128 human breast carcinomas revealed that AEBS activity was present and could exceed ERc activity. Importantly, the partition of significant AE away from ERc was observed in human specimens. These observations identify a biochemical mechanism for antiestrogen resistance through which AE access to ERc can be totally incapacitated while sensitivity to estrogens continues. These observations indicate that AEBS activity, in addition to ERc activity, may provide helpful information for predicting the response of certain cancers to hormonal therapy.