title: Association of drug transporter expression with mortality and progression-free survival in stage IV head and neck squamous cell carcinoma.
abstract: Drug transporters such as P-glycoprotein (ABCB1) have been associated with chemotherapy resistance and are considered unfavorable prognostic factors for survival of cancer patients. Analyzing mRNA expression levels of a subset of drug transporters by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or protein expression by tissue microarray (TMA) in tumor samples of therapy naïve stage IV head and neck squamous cell carcinoma (HNSCC) (qRT-PCR, n = 40; TMA, n = 61), this in situ study re-examined the significance of transporter expression for progression-free survival (PFS) and overall survival (OS). Data from The Cancer Genome Atlas database was used to externally validate the respective findings (n = 317). In general, HNSCC tended to lower expression of drug transporters compared to normal epithelium. High ABCB1 mRNA tumor expression was associated with both favorable progression-free survival (PFS, p = 0.0357) and overall survival (OS, p = 0.0535). Similar results were obtained for the mRNA of ABCC1 (MRP1, multidrug resistance-associated protein 1; PFS, p = 0.0183; OS, p = 0.038). In contrast, protein expression of ATP7b (copper transporter ATP7b), mRNA expression of ABCG2 (BCRP, breast cancer resistance protein), ABCC2 (MRP2), and SLC31A1 (hCTR1, human copper transporter 1) did not correlate with survival. Cluster analysis however revealed that simultaneous high expression of SLC31A1, ABCC2, and ABCG2 indicates poor survival of HNSCC patients. In conclusion, this study militates against the intuitive dogma where high expression of drug efflux transporters indicates poor survival, but demonstrates that expression of single drug transporters might indicate even improved survival. Prospectively, combined analysis of the 'transportome' should rather be performed as it likely unravels meaningful data on the impact of drug transporters on survival of patients with HNSCC.
authors.affiliation: Experimental Neurosurgery Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany; Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Warta
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Theile
authors.affiliation: Tissue Bank of the National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany; Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Mogler
authors.affiliation: Tissue Bank of the National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany; Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany; Hamamatsu Tissue Imaging and Analysis Center, BIOQUANT, University of Heidelberg, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Hamamatsu Tissue Imaging and Analysis Center, BIOQUANT, University of Heidelberg, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.affiliation: Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Plinkert
authors.affiliation: Experimental Neurosurgery Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany; Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dyckhoff
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D000073840:Copper-Transporting ATPases; D030541:Databases, Genetic; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D000077195:Squamous Cell Carcinoma of Head and Neck; D046888:Tissue Array Analysis
chemical_list: C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D027682:Cation Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases