MECHANISM FOR MAINTENANCE OF HIGH BREAST-TUMOR ESTRADIOL CONCENTRATIONS IN THE ABSENCE OF OVARIAN-FUNCTION - ROLE OF VERY HIGH-AFFINITY TISSUE UPTAKE

Breast tumors from postmenopausal women contain levels of estradiol si milar to those in premenopausal patients even though serum estradiol l evels fall by an order of magnitude upon cessation of ovarian function . The present study sought to examine enhanced uptake from plasma as o ne potential mechanism for maintenance of high tissue estradiol levels in postmenopausal patients. Accordingly, we used osmotic minipumps to continuously infuse estradiol (E(2)) at rates producing serum concent rations ranging from pre- to postmenopausal levels for two weeks to oo phorectomized Sprague-Dawley rats bearing nitrosomethylurea-induced ma mmary tumors. We then measured E(2) concentrations in various tissues and sera and reasoned that tissue affinities for estradiol could be di rectly calculated from in vivo measurements by adapting Scatchard anal ysis to steroid infusion data. Using this method, we demonstrated a ve ry high affinity estradiol binding component with a K-d two orders of magnitude higher (i.e., 0.35 x 10(-12) M) than determined with standar d in vitro techniques. A second estradiol binding component with the e xpected K-d of 1 x 10(-10) M was also present. Estradiol bound to both classes of binding sites could be 98% displaced with diethylstilbestr ol within a 6-hr period. In vivo steroid binding off-times calculated from log-linear slopes averaged approximately 60 min. These data demon strated that the actual E(2) binding affinity in target tissues in viv o, especially at low estrogen concentrations, is much higher than usua lly estimated from standard, in vitro estrogen receptor assays. These observations provide one mechanism to explain why estradiol concentrat ions remain high in breast cancer tissue from postmenopausal women and consequently can stimulate tumor proliferation.