ESTROGENIC EFFECTS OF PHYSIOLOGICAL CONCENTRATIONS OF 5-ANDROSTENE-3-BETA,17-BETA-DIOL AND ITS METABOLISM IN MCF7 HUMAN-BREAST CANCER-CELLS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (11) , 4720-4726
Abstract
5-Androstene-3.beta.,17.beta.-diol (ADIOL) has a high affinity for the estrogen receptor and translocates it to the nucleus in vitro and in vivo. This compound and related C19 .DELTA.5-steroids of adrenal origin were examined for their ability to induce the synthesis in MCF7 cells of an estrogen-dependent secreted glycoprotein (MW 46,000). Concentrations required for half-maximum induction were 2 nM for ADIOL and 500 nM for dehydroepiandrosterone (DHEA). Dehydroepiandrosterone sulfate showed weak inducing ability at concentrations of 1 .mu.M or greater. The induction by ADIOL was unaffected by the presence of an aromatase inhibitor, and 5.alpha.-androstane-3.beta.,17.beta.-diol, which cannot be aromatized, also induced the MW 46,000 protein at low concentrations. When cells were exposed to 10 nM [3H]ADIOL, the cytosol and nuclear fractions contained [3H]ADIOL resistant to charcoal adsorption. The bound [3H]ADIOL in the cytosol and nucleus was displaceable by 17.beta.-estradiol and tamoxifen, suggesting that it was binding to the estrogen receptor. [3H]ADIOL was metabolized to its 3.beta.-sulfate, which was excreted into the medium, and to [3H]DHEA, which was found in the cells and the medium as free DHEA and its 3.beta.-sulfate. [3H]DHEA was metabolized by the cells to its 3.beta.-sulfate, to free ADIOL, and to the 3.beta.-sulfate of ADIOL. ADIOL is effective as an estrogen in MCF7 cells at a concentration of 2 nM, which is within the range found in the blood of normal women. Sulfurylation is a major route of inactivation of 3.beta.-hydroxy .DELTA.5-steroids in MCF7 cells.