title: Selenium disrupts estrogen signaling by altering estrogen receptor expression and ligand binding in human breast cancer cells.
abstract: Cancer prevention studies suggest that selenium is effective in reducing the incidence of cancers including prostate, colon, and lung cancers. Previous reports showed that selenium inhibits premalignant human breast MCF-10AT1 and MCF10AT3B cell growth in vitro and reduces mammary tumor incidence after exposure to carcinogens in tumor models. Because estrogen is critical to the development and differentiation of estrogen target tissues, including the breast, the present study was designed to examine the effect of selenium on estrogen receptor (ER) expression and activation using methylseleninic acid (MSA), an active form of selenium in vitro. Selenium decreased the levels of expression of ERalpha mRNA and protein and reduced the binding of labeled estradiol to estrogen receptor in MCF-7 cells. Selenium inhibited the trans-activating activity of estrogen receptor in MCF-7 cells expressing functional estrogen receptor using a luciferase reporter construct linked to estrogen responsive element. Selenium decreased the binding of estrogen receptor to the estrogen responsive element site using an electrophoretic mobility gel shift assay. Selenium suppressed estrogen induction of the endogenous target gene c-myc. In contrast to the effect on ERalpha in MCF-7 cells, selenium increased ERbeta mRNA expression in MDA-MB231 human breast cancer cells. Thus, differential regulation of ERalpha and ERbeta in breast cancer cells may represent a novel mechanism of selenium action and provide a rationale for selenium breast cancer prevention trial.
authors.affiliation: Department of Medicine, Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, NY 14263, USA.
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.forename: Nagalakshmi
authors.initials: N
authors.lastname: Nadiminty
authors.forename: Xiu Xian
authors.initials: XX
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Lou
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Clement
authors.initials: C
authors.lastname: Ip
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Onate
authors.forename: Allen C
authors.initials: AC
authors.lastname: Gao
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D016566:Organoselenium Compounds / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; C489427:MYC protein, human; D016566:Organoselenium Compounds; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D004958:Estradiol; C008493:methylselenic acid