title: Multidrug resistance transporter profile reveals MDR3 as a marker for stratification of blastemal Wilms tumour patients.
abstract: Wilms tumour (WT) is the most common renal tumour in children. Most WT patients respond to chemotherapy, but subsets of tumours develop resistance to chemotherapeutic agents, which is a major obstacle in their successful treatment. Multidrug resistance transporters play a crucial role in the development of resistance in cancer due to the efflux of anticancer agents out of cells. The aim of this study was to explore several human multidrug resistance transporters in 46 WT and 40 non-neoplastic control tissues (normal kidney) from patients selected after chemotherapy treatment SIOP 93-01, SIOP 2001. Our data showed that the majority of the studied multidrug resistance transporters were downregulated or unchanged between tumours and control tissues. However, BCRP1, MDR3 and MRP1 were upregulated in tumours versus control tissues. MDR3 and MRP1 overexpression correlated with high-risk tumours (SIOP classification) (p = 0.0022 and p < 0.0001, respectively) and the time of disease-free survival was significantly shorter in patients with high transcript levels of MDR3 (p = 0.0359). MDR3 and MRP1 play a role in drug resistance in WT treatment, probably by alteration of an unspecific drug excretion system. Besides, within the blastemal subtype, we observed patients with low MDR3 expression were significantly associated with a better outcome than patients with high MDR3 expression. We could define two types of blastemal WT associated with different disease outcomes, enabling the stratification of blastemal WT patients based on the expression levels of the multidrug resistance transporter MDR3.
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Hontecillas-Prieto
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Garcia-Dominguez
authors.affiliation: Pathology Unit, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Diego Pascual
authors.initials: DP
authors.lastname: Vaca
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Garcia-Mejias
authors.affiliation: Pathology Unit, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Marcilla
authors.affiliation: Pediatric Oncology Unit, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Gema L
authors.initials: GL
authors.lastname: Ramirez-Villar
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.|Pathology Unit, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Saez
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.|Pathology Unit, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: de Álava
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003609:Dactinomycin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007223:Infant; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009392:Nephrectomy / Q000379:methods; D017063:Outcome Assessment, Health Care / Q000379:methods; D011379:Prognosis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis / Q000379:methods; D014750:Vincristine / Q000008:administration & dosage; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism / Q000628:therapy
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D014408:Biomarkers, Tumor; D003609:Dactinomycin; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014750:Vincristine; C095122:multidrug resistance protein 3; C421109:multidrug resistance-associated protein 1
keywords: MDR3; MRP1; Wilms tumours; blastemal stratification; multidrug resistance transporters