Association of drug transporter expression with mortality and progression-free survival in stage IV head and neck squamous cell carcinoma

• Published in: PloS one 2014-10, Vol.9 (9), p.e108908-e108908
• Main Authors: Warta, Rolf, Theile, Dirk, Mogler, Carolin, Herpel, Esther, Grabe, Niels, Lahrmann, Bernd, Plinkert, Peter K, Herold-Mende, Christel, Weiss, Johanna, Dyckhoff, Gerhard
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Aged; Aged, 80 and over; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biology; Biology and Life Sciences; Breast cancer; Cancer; Cancer genetics; Cancer therapies; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cell survival; Chemoresistance; Chemotherapy; Cluster Analysis; Copper; Copper-transporting ATPases; Correlation analysis; Databases, Genetic; Development and progression; Disease-Free Survival; DNA microarrays; Drug resistance; Efflux; Epithelium; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Glycoproteins; Head; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Health aspects; Humans; Immunohistochemistry; Male; Medicine and Health Sciences; Metastasis; Middle Aged; Mortality; Multidrug resistance; Neoplasm Staging; Neurosurgery; Otolaryngology; P-Glycoprotein; Pathology; Patients; Polymerase chain reaction; Protein arrays; Proteins; Reproducibility of Results; Reverse transcription; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Stem cells; Surgery; Survival; Survival analysis; Tissue Array Analysis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0108908

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.