Studies on estrogen receptors and regression in human breast cancer

Estradiol receptors were studied both qualitatively and quantitatively in 650 cases of breast cancer to obtain information on molecular forms and relationship with response to endocrine therapy. Cytosol estradiol receptor (ERC) was assayed by a charcoal method following incubations with 3H-estradiol and also by chromatography on Sephacryl columns. Results were classified as positive (10 fmoles/mg P and up), borderline (3-10 fmoles) and negative (0-3 fmoles). It was found that 44.6% of tumors were positive, 14.15% were borderline, and 41.2% were negative. Qualitatively, two major molecular forms of ERC were identified with molecular weights 31,000 and approximately 250,000. ERC level and response to endocrine therapy were correlated in a group of 52 patients. Response rate to hormonal therapy only was 59% in the ERC-positive, 28% in the borderline, and 9% in the ERC-negative group. Combination therapy, including endocrine manipulation, chemotherapy, and/or radiation improved response rates to 66% in the ERC-positive, 40% in the borderline, and 33% in the ERC-negative group. Defects in the translocation of the cytosol estradiol receptor (ERC)-estradiol complex to the nucleus could partly explain the failure of endocrine therapy in 40% of patients with significant ERC. To examine this possibility, 98 cases of breast cancer were examined for both ERC and nuclear translocation of estradiol (ERN). Nuclei were isolated from the low speed sediment and incubated with the ERC-3H-estradiol complex in the presence and absence of an estrogen competitor. After incubation, ERN was extracted from the nuclei and expressed as specifically bound estradiol, fmoles/mg DNA. Of 44 cases with significant ERC, nine had no ERN (20%). In the borderline group of 23 cases, eight had no ERN (34%), and of the 31 cases with zero or negligible ERC 27 had no ERN (87%). Results indicate that ERC-negative cases should be excluded from hormonal therapy and appear to benefit most from chemo- and/or radiation therapy. The absence of ERN in a significant proportion of ERC-positive cases probably contributes to the failure of hormonal manipulation in such patients. The results indicate that the determination of both ERC and ERN could improve the selection of patients for endocrine therapy.