Gonadotropins stimulate growth of MCF-7 human breast cancer cells by promoting intracellular conversion of adrenal androgens to estrogens

Estrogen receptor (ER)-positive breast cancers initially respond well to es trogen ablation treatment but finally acquire refractoriness, the phenomeno n that is a major clinical problem. Because some breast cancers synthesize estradiol (E-2) and E-2 synthesis is regulated by gonadotropins in normal o varies, and because circulating gonadotropins are elevated in postmenopausa l women and during estrogen ablation treatment, we hypothesized that gonado tropins might modulate estrogen synthesis/metabolism in breast cancer tissu e as well. To test this possibility, MCF-7 cells were treated with dehydroe piandrosterone (DHEA) or human chorionic gonadotropin (hCG; similar to LH), each alone or in combination. Cell growth (3-day treatment) was assayed by the MTT method and estrogen synthesis (24-hour treatment) was measured usi ng the ERE-luciferase reporter system. First, MCF-7 cell growth was stimula ted by DHEA in a concentration-dependent manner with a maximal effect at 10 (-4) M. Although hCG alone did not have a significant proliferative effect, hCG significantly and dose dependently stimulated MCF-7 cell growth in the presence of a submaximal concentration of DHEA (10(-7) M). This stimulator y effect of DHEA and hCG was blocked by a pure antiestrogen ICI182,780 and an aromatase inhibitor, arimidex. Using MCF-7 cells transfected with the ER E-luciferase reporter system, hCG treatment was shown to increase ERE-media ted transcription. These results indicate that MCF-7 cells intrinsically co nverted DHEA into E-2 upon hCG stimulation, then grew their own cells DHEA- and hCG-dependently. We conclude that gonadotropins can act on breast canc er cells and accelerate conversion of DHEA into estrogens, thereby stimulat ing growth of estrogen-dependent tumor cells. This phenomenon, at least in part, could explain: (1) an increased tissue concentration of Ep in postmen opausal breast cancer; (2) acquisition of hormone refractoriness during est rogen ablation treatment, and (3) the effectiveness of GnRH antagonist/supe ragonist in some postmenopausal breast cancer patients. Copyright (C) 2000 S. Karger AG, Basel.