Association of breast cancer resistance protein/ABCG2 phenotypes and novel promoter and intron 1 single nucleotide polymorphisms.
The hypothesis was tested that sequence diversity in breast cancer resistance protein (BCRP)'s cis-regulatory region is a significant determinant of BCRP expression. The BCRP promoter and intron 1 were resequenced in lymphoblast DNA from the polymorphism discovery resource (PDR) 44 subset. BCRP single nucleotide polymorphisms (SNPs) were genotyped in donor human livers, intestines, and lymphoblasts quantitatively phenotyped for BCRP mRNA expression. Carriers of the -15622C>T SNP had lower BCRP expression in multiple tissues. The intron 1 SNP 16702C>T was associated with high expression in livers; 1143G>A was associated with low expression in intestine; 12283T>C was associated with higher expression in the PDR44 and White livers. The -15994C>T promoter SNP was significantly associated with higher BCRP expression in multiple tissues. Patients with the -15994C>T genotype had substantially higher clearance of p.o. imatinib. We next determined whether BCRP expression was related to polymorphic alternative splicing or alternative promoter use. Liver polymorphically expressed an alternatively spliced mRNA [splice variant (SV) 1] skipping exon 2. Although SV1+ livers did not uniformly carry the exon 2 G34A allele, 90% of G34A livers expressed SV1 (versus 4% of 34GG livers). BCRP mRNA was significantly lower among Hispanic livers with the G34A variant genotype and may be due, in part, to polymorphic exon 2 splicing. Analysis of allele expression imbalance (AEI) showed that PDR44 samples with AEI had lower BCRP mRNA expression; however, no linked cis-polymorphisms were identified. BCRP used multiple promoters, and livers differentially using alternative exon 1b had lower BCRP. In conclusion, BCRP expression in lymphoblasts, liver, and intestine is associated with novel promoter and intron 1 SNPs.
Poonkuzhali
Balasubramanian
B
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Lamba
Jatinder
J
Strom
Stephen
S
Sparreboom
Alex
A
Thummel
Kenneth
K
Watkins
Paul
P
Schuetz
Erin
E
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D000595:Amino Acid Sequence / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins