Contribution of α 2-adrenoceptors to the mitogenic effect of catecholestrogen in human breast cancer MCF-7 cells

Abstract

Catecholestrogens are estrogen metabolites formed by hydroxylation of 17β-estradiol and estrone at either the C-2 or C-4 position, rivaling the parent estrogens in concentration. The objective of the present work was to assess if their catechol group could make them induce proliferation of human breast cancer cells via α 2-adrenoceptors. In competition studies in human breast cancer MCF-7 cells, high concentrations of 2-hydroxy-estradiol (2-OH-E 2), 2-hydroxy-estrone (2-OH-E 1) and 4-hydroxy-estrone (4-OH-E 1) competed for [ 3H]-rauwolscine binding, whereas 4-hydroxy-estradiol (4-OH-E 2) did not. The contribution of α 2-adrenoceptors and estrogen receptors (ERs) in proliferation enhancement was analyzed with specific antagonists. The specific α 2-adrenergic antagonist yohimbine partially reversed the effect of catecholestrogens except 4-OH-E 2. The selective ER downregulator ICI-182780 or fulvestrant partially or totally reversed the effect of all hydroxylated catecholestrogens. When analyzing the effect of the combination of both antagonists in MCF-7, the contribution of the α 2-adrenoceptors and ERs for 2-OH-E 2, 2-OH-E 1 and 4-OH-E 1 was mixed, whereas for 4-OH-E 2, the only receptor implied was an ER. In MDA-MB-231 cells (ER-α negative) the proliferation stimulation by these three catecholestrogens and reversal by the adrenergic antagonist was also observed. It can be concluded that α 2-adrenoceptors contribute at least in part to the mitogenic effect of 2-OH-E 2, 2-OH-E 1 and 4-OH-E 1.