title: Resistance to topoisomerase poisons due to loss of DNA mismatch repair.
abstract: Sporadic breast carcinomas demonstrate microsatellite instability, reflecting the presence of DNA mismatch repair-deficient cells, in about one fourth of cases at the time of diagnosis. Loss of DNA mismatch repair has been reported to result in resistance not only to cisplatin and alkylating agents but also to the topoisomerase II poison doxorubicin, suggesting an association between DNA mismatch repair and topoisomerase II poison-induced cytotoxicity. Our study investigates the relationship between loss of MSH2 or MLH1 function and sensitivity to the topoisomerase I and II poisons, and to the taxanes, 2 classes of cytotoxic drugs commonly used in breast cancer. Two pairs of cell lines proficient and deficient in mismatch repair due to loss of either MSH2 or MLH1 function were used. Loss of either MSH2 or MLH1 function resulted in resistance to the topoisomerase II poisons doxorubicin, epirubicin and mitoxantrone, whereas only loss of MLH1 function was associated with low-level resistance to the topoisomerase I poisons camptothecin and topotecan. In contrast, there was no resistance to docetaxel and paclitaxel. Our data support the hypothesis that both MSH2 and MLH1 are involved in topoisomerase II poison-mediated cytotoxicity, whereas only MLH1 is involved in topoisomerase I poison-mediated cytotoxicity. Since our study shows that loss of DNA mismatch repair does not result in resistance to the taxanes, these drugs can be recommended for use in breast cancer deficient in mismatch repair.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Fedier
authors.forename: V A
authors.initials: VA
authors.lastname: Schwarz
authors.forename: H
authors.initials: H
authors.lastname: Walt
authors.forename: R D
authors.initials: RD
authors.lastname: Carpini
authors.forename: U
authors.initials: U
authors.lastname: Haller
authors.forename: D
authors.initials: D
authors.lastname: Fink
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D020137:Base Pair Mismatch; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D008942:Mitoxantrone / Q000494:pharmacology; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000502:physiology; D009687:Nuclear Proteins; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D043823:Taxoids; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000093542:Gemcitabine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D043823:Taxoids; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D003841:Deoxycytidine; D000077143:Docetaxel; D015251:Epirubicin; D004317:Doxorubicin; D008942:Mitoxantrone; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D017239:Paclitaxel; D000093542:Gemcitabine