ESTROGEN-RECEPTOR FUNCTIONAL STATUS IN HUMAN BREAST-CANCER

Estrogen receptors (ER) are detected in 50-85% of all breast tumors, a nd are clinically important because they tend to identify patients wit h a higher probability of responding to hormonal or endocrine manipula tions. However, similar to 30-40% of all ER(+) patients do not respond to hormonal manipulations. The lack of response to hormonal manipulat ions in ER(+) patients could be the result of nonfunctional ER, as det ermined by its inability to recognize and bind to specific DNA-respons ive elements and/or its inability to recruit other transcriptional act ivation factors. The functional status of ER in 34 human breast tumors was assessed by determining the structural integrity of the ER DNA-bi nding domain using site-directed monoclonal anti-estrogen receptor ant ibody and sucrose density gradient analysis. Based on the fraction of ER containing an intact DNA-binding domain, the tumors were classified into three groups: group I with >65% of intact ER, group II with >30% of intact ER, and group III with <30% of intact ER. Clinical and path ologic data were obtained only for patients who were treated with the anti-estrogen tamoxifen and correlated with ER functional status. In g roup I, 11 of 13 (84.6%) patients were responsive to hormonal therapy with favorable clinical outcome; two patients had unfavorable clinical outcome. In group II, 13 of 15 patients (86.7%) had favorable clinica l outcome and two patients (13.3%) had unfavorable outcome. In group I II, three of six patients appeared to be hormone responsive with favor able clinical outcome, and three of the patients in this group had unf avorable response to therapy. ER functional status may be linked to ho rmone responsiveness in breast cancer and the resistance of some ER(+) tumors to anti-estrogen treatment may be explained, in part, by dysfu nctional ER. This approach may permit the development of new clinical assays based on ER functional status, which could facilitate selection of patients who are likely to benefit from anti-estrogen therapy.