title: Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP.
abstract: Intrinsic or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with solid carcinoma. Cisplatin is one of the most effective chemotherapeutic agents for treating ovarian carcinoma. Recently, copper-transporting P-type adenosine triphosphatase (ATP7B) has been demonstrated as one of the genes responsible for cisplatin resistance in vitro. We hypothesized that the expression of ATP7B gene increases resistance to cisplatin in ovarian carcinoma and a priori knowledge of its expression is important for the choice of therapy. The aim of our study was to assess the role of ATP7B gene in ovarian carcinoma and compare its expression with those of multidrug resistance-related transporters such as MDR1, MRP1, MRP2, LRP and BCRP genes. The transporters' gene expression profiles from 82 patients treated with cisplatin-based chemotherapy after surgery were assessed by RT-PCR. We did not observe any significant correlation between ATP7B gene expression and those of MDR1, MRP1, MRP2, LRP or BCRP. The expression level of ATP7B gene was significantly increased (p < 0.05) in patients with moderately-/poorly-differentiated ovarian carcinomas treated with cisplatin-based chemotherapy, thus ATP7B may serve as an independent prognostic factor in these patients. In contrast, the expression level of MDR1, MRP1, MRP2, LRP and BCRP genes were not prognostic indicators of disease. These findings suggest that ATP7B gene may be considered as a novel chemoresistance marker and that inhibitor(s) of ATP7B might be useful, in patients with ovarian carcinoma treated with cisplatin-based chemotherapy.
authors.affiliation: Department of Pathology Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kanzaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Kohji
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takebayashi
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D027682:Cation Transport Proteins / Q000235:genetics*; D019742:Chemokines, CC; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D000073840:Copper-Transporting ATPases; D016207:Cytokines / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR; D006801:Humans; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface; D012008:Recurrence; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D060245:Tetraspanin 29
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D015415:Biomarkers; C554869:CD9 protein, human; D027682:Cation Transport Proteins; C095218:Ccl9 protein, mouse; C554870:Cd9 protein, mouse; D019742:Chemokines, CC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D060245:Tetraspanin 29; C516841:PTPRA protein, human; D017027:Protein Tyrosine Phosphatases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D002945:Cisplatin