The efflux transporter breast cancer resistance protein BCRP/ABCG2 is well-known for its contribution to multi-drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. This study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC-cohorts (cohort-1 (KIRC/TCGA): n=453, cohort-2: n=64) were investigated to elucidate BCRP/ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib-treated ccRCC-cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ABCB1 were additionally evaluated in these cohorts. In independent ccRCC-cohorts, low BCRP/ABCG2 and MDR1/ABCB1 mRNA and protein expression were associated with severity (e.g. tumor stage) of ccRCC and poor cancer-specific survival. BCRP/ABCG2 and MDR1/ABCB1 mRNA expression were linked to decreased progression-free survival following sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ABCG2 expression only moderately. miR-212-3p and miR-132-3p were identified to regulate BCRP/ABCG2 posttranscriptionally by interaction with the ABCG2 3'UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ABCG2 expression, miR-212-3p and miR-132-3p were identified to contribute to posttranscriptional regulation of BCRP/ABCG2. This article is protected by copyright. All rights reserved.
International journal of cancer. 2018 Aug 02 [Epub ahead of print]
Anna Reustle, Pascale Fisel, Olga Renner, Florian Büttner, Stefan Winter, Steffen Rausch, Stephan Kruck, Anne T Nies, Jörg Hennenlotter, Marcus Scharpf, Falko Fend, Arnulf Stenzl, Jens Bedke, Matthias Schwab, Elke Schaeffeler
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany., Department of Urology, University Hospital Tübingen, Tübingen, Germany., Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.