title: Estrogen-mediated post transcriptional down-regulation of P-glycoprotein in MDR1-transduced human breast cancer cells.
abstract: The human multidrug resistance gene 1 (MDR1) encodes the plasma membrane P-glycoprotein (P-gp/ABCB1) that functions as an efflux pump for various anticancer agents. We recently reported that estrogens down-regulate the expression of breast cancer resistance protein (BCRP/ABCG2). In our present study we demonstrate that estrogens also down-regulate P-gp expression in the MDR1-transduced, estrogen receptor alpha (ER-alpha)-positive human breast cancer cells, MCF-7/MDR and T-47D/MDR. The P-gp expression levels in MCF-7/MDR cells treated with 100 pM estradiol were found to be 10-20-fold lower than the levels in these same cells that were cultured without estradiol. In contrast, estradiol did not affect the P-gp expression levels in the ER-alpha-negative cancer cells, MDA-MB-231/MDR and NCI/ADR-RES. Estrone and diethylstilbestrol were also found to down-regulate P-gp in MCF-7/MDR cells, but progesterone treatment did not produce this effect. Tamoxifen reversed the estradiol-mediated down-regulation of P-gp in MCF-7/MDR cells, suggesting that ER-alpha activity is necessary for the effects of estradiol upon P-gp. However, estradiol was found not to alter the MDR1 transcript levels in either MCF-7/MDR and T-47D/MDR cells, suggesting that post-transcriptional mechanisms underlie its effects upon P-gp down-regulation. MCF-7/MDR cells also showed eight-fold higher sensitivity to vincristine when treated with 100 pM estradiol, than when treated with 1 pM estradiol. These results may serve to provide a better understanding of the expression control of ABC transporters, and possibly allow for the establishment of new cancer chemotherapy strategies that would control P-gp expression in breast cancer cells and thereby increase their sensitivity to MDR1-related anticancer agents.
authors.affiliation: Department of Chemotherapy, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minatoku, Tokyo 105-8512, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Mutoh
authors.forename: Satomi
authors.initials: S
authors.lastname: Tsukahara
authors.forename: Junko
authors.initials: J
authors.lastname: Mitsuhashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Katayama
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001692:Biological Transport; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D047628:Estrogen Receptor alpha; D004967:Estrogens; D013629:Tamoxifen; D004958:Estradiol; D014750:Vincristine