title: Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells.
abstract: Recent studies have shown that the Bcl-2 protein suppresses programmed cell death or apoptosis induced by a variety of stimuli including chemotherapeutic drugs. Because estrogen promotes the survival of estrogen-dependent breast cancer cells in vivo, we investigated whether estrogen might regulate levels of Bcl-2 gene expression in an estrogen-responsive human breast cancer cell line. Estrogen receptor-positive MCF-7 human breast cancer cells cultured in the presence of estrogen express the 8.5-kb Bcl-2 mRNA transcript. Depletion of estrogen from the medium results in loss of expression of the mRNA, whereas reexposure to estrogen markedly induces the Bcl-2 transcript. The changes in Bcl-2 mRNA are paralleled by changes in Bcl-2 protein levels. Estrogen-induced increases in Bcl-2 are significantly inhibited by inclusion of the pure antiestrogen ICI 164,384 in the medium. The Bax protein that heterodimerizes with Bcl-2 and promotes cell death is expressed in MCF-7 cells grown in the presence of estrogen and is unaffected by culture in estrogen-free medium. Estrogen depletion doubles the sensitivity of MCF-7 cells to the cytotoxic effects of Adriamycin compared with cells cultured in medium supplemented with estrogen, consistent with a decrease in the Bcl-2 levels. MCF-7 cells treated simultaneously with estrogen and ICI 164,384 exhibit markedly lower resistance to Adriamycin compared with cells treated with estrogen alone. In the absence of estrogen, MCF-7 cells transfected with Bcl-2 expression plasmids display a marked increase in resistance to Adriamycin. In the presence of estrogen, MCF-7 cells expressing Bcl-2 antisense transcripts are rendered twice as sensitive to acute Adriamycin cytotoxicity as a control clone. We conclude that estrogen can promote resistance of estrogen receptor bearing human breast cancer cells to chemotherapeutic drugs through a mechanism that involves regulation of the Bcl-2 proto-oncogene.
authors.affiliation: Department of Pharmacology, University of Ottawa, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Teixeira
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
authors.forename: M A
authors.initials: MA
authors.lastname: Pratt
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D004967:Estrogens; C000715470:MAS1 protein, human; D053284:Polyunsaturated Alkamides; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D004958:Estradiol; D004317:Doxorubicin; C051781:ICI 164384