Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

Abstract

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. Our 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 after 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.

Germline variant burden in multidrug resistance transporters is a therapy‐specific predictor of survival in breast cancer patients

“…In addition, our previous work supports the data for ccRCC since germline and somatic variants could not explain aberrant expression of ABCG2 and consequently patient survival. 47 Notably, while variant burden in ABCC1 and ABCG2 showed a monotone association with DSS in the overall BRCA cohort, subgroup analyses revealed nonmonotone relationships in the drug subgroups. As the genomic landscape of ABCC1 and ABCG2 is complex with a multitude of lowfrequency haplotypes, we speculate that specific haplotypes of low-effect size variants might drug-specifically modulate DSS.…”

“…Importantly, ABC variability was not predictive of outcomes in patients with cancer types that are primarily treated by surgery, such as clear cell renal cell carcinoma and hepatocellular carcinoma (permutation p > 0.05), further corroborating the validity of our approach. In addition, our previous work supports the data for ccRCC since germline and somatic variants could not explain aberrant expression of ABCG2 and consequently patient survival …”

Aberrant DNA Methylation of ABC Transporters in Cancer

“…There is growing evidence that DNA methylation contributes to regulation of ABCG2 (see Section 4 ). miRNAs (miR-132-3p, miR-212-3p) have been found to be involved in post-transcriptional regulation of ABCG2 in clear cell renal cell carcinoma [ 79 ].…”

“…Aberrant DNA methylation has already been detected in various solid and hematological cancers. In the following, we summarize and discuss these findings, starting with thoracic malignancies [ 132 , 142 , 145 , 147 , 150 ], continuing with breast cancer [ 129 , 130 , 131 , 138 , 139 , 140 , 141 , 142 , 147 , 151 , 152 ], colorectal cancer [ 127 , 143 , 148 ], upper gastrointestinal cancer [ 133 , 134 , 153 , 154 , 155 , 156 ], genitourinary cancers [ 79 , 93 , 136 , 137 , 146 , 157 , 158 , 159 , 160 , 161 , 162 , 163 ], gynecological cancers [ 139 , 142 , 147 , 164 ], tumors of the central nervous system [ 144 ], ending with hematological malignancies [ 126 , 127 , 128 , 133 , 135 , 142 , 147 , 149 , 165 , 166 ].…”

“…Reustle et al aimed to elucidate the biological relevance and the regulatory mechanism of ABCG2 in clear cell renal cell carcinoma [ 79 ]. The study comprised five renal cancer cell lines (ACHN, A-498, Caki-1, Caki-2, and 786-O), a patient cohort from TCGA (453 patients), an own cohort (64 patients), and an independent set of transcriptome data (53 patients with metastases, who had been treated first-line with sunitinib, a multityrosine kinase inhibitor).…”