title: Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells.
abstract: The estrogen responsive human breast cancer MCF-7 cell culture was examined for its response to 2-hydroxyestrone a principal metabolite of estradiol. Addition of 2-hydroxyestrone to the cell cultures in concentration of 10(-9) - 10(-6) M had no effect on cell growth and proliferation because of rapid O-methylation of the catechol estrogen by catechol O-methyltransferase which is highly active in these cells. In the presence of quinalizarin, a potent catechol O-methyltransferase inhibitor which reduces the O-methylation of the steroid, 10(-7) M and 10(-8) M 2-hydroxyestrone markedly suppresses the growth and proliferation of the cells. The tumor cell growth-inhibitory action of the catechol estrogen was neutralized by the presence of 10(-9) M estradiol. The catechol estrogen inhibition of cell growth is not observed in the estrogen receptor-negative human breast cancer cell lines MDA-MB-231 and MDA-MB-330 providing evidence that the inhibition is specific and is estrogen receptor-mediated. In contrast, the 16 alpha-hydroxylated metabolites of estradiol, estriol and 16 alpha-hydroxyestrone, are effective stimulators of MCF-7 cell proliferation with the latter exhibiting potency in excess of that expected from its estrogen receptor affinity. The present results represent the first observation of a specific receptor-mediated antiestrogenic action of 2-hydroxyestrone and suggest that the physiological regulation of the agonist activity of the primary estrogen may involve in situ generation of catechol estrogen.
mesh_terms: D001943:Breast Neoplasms / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists; D002393:Estrogens, Catechol / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D006894:Hydroxyestrones / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D011960:Receptors, Estrogen / Q000502:physiology
chemical_list: D004965:Estrogen Antagonists; D002393:Estrogens, Catechol; D006894:Hydroxyestrones; D011960:Receptors, Estrogen; D004970:Estrone; D004958:Estradiol; C024980:2-hydroxyestrone