title: The phytoestrogen genistein enhances multidrug resistance in breast cancer cell lines by translational regulation of ABC transporters.
abstract: Breast cancer is the most frequent malignancy in women. Multidrug resistance due to overexpression of ABC drug transporters is a common cause of chemotherapy failure and disease recurrence. Genistein (GNT) is a phytoestrogen present in soybeans and hormone supplements. We investigated the effect of GNT on the expression and function of ABC transporters in MCF-7 and MDA-MB-231 breast cancer cell lines. Results demonstrated an induction at the protein level of ABCC1 and ABCG2 and of ABCC1 in MCF-7 and MDA-MB-231, respectively. MCF-7 cells showed a concomitant increase in doxorubicin and mitoxantrone efflux and resistance, dependent on ABCG2 activity. ABCC1 induction by GNT in MDA-MB-231 cells modified neither drug efflux nor chemoresistance due to simultaneous acute inhibition of the transporter activity by GNT. All inductions took place at the translational level, as no increment in mRNA was observed and protein increase was prevented by cycloheximide. miR-181a, already demonstrated to inhibit ABCG2 translation, was down-regulated by GNT, explaining translational induction. Effects were independent of classical estrogen receptors. Results suggest potential nutrient-drug interactions that could threaten chemotherapy efficacy, especially in ABCG2-expressing tumors treated with substrates of this transporter.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rigalli
authors.affiliation: Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Guillermo Nicolás
authors.initials: GN
authors.lastname: Tocchetti
authors.affiliation: Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Maite Rocío
authors.initials: MR
authors.lastname: Arana
authors.affiliation: Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Silvina Stella Maris
authors.initials: SS
authors.lastname: Villanueva
authors.affiliation: Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: Viviana Alicia
authors.initials: VA
authors.lastname: Catania
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Theile
authors.affiliation: Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Suipacha 570, 2000 Rosario, Argentina.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Ruiz
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: johanna.weiss@med.uni-heidelberg.de.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D018565:Food-Drug Interactions; D015972:Gene Expression Regulation, Neoplastic; D019833:Genistein / Q000633:toxicity*; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D048789:Phytoestrogens / Q000633:toxicity*; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018570:Risk Assessment; D015854:Up-Regulation
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D004317:Doxorubicin; D019833:Genistein; D035683:MicroRNAs; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D048789:Phytoestrogens; D011500:Protein Synthesis Inhibitors; C116614:ABCG2 protein, human; C540193:MIrn181 microRNA, human; C421109:multidrug resistance-associated protein 1
keywords: Breast cancer; Chemoresistance; Genistein; Multidrug resistance; Translational regulation