The Identification of Two Germ-line Mutations in the Human Breast Cancer Resistance Protein Gene that Result in the Expression of a Low/Non-functional Protein
The Identification of Two Germ-line Mutations in the Human Breast Cancer Resistance Protein Gene that Result in the Expression of a Low/Non-functional Protein
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DOI：
10.1007/s11095-007-9235-2
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发表时间：
2007-03
影响因子：
3.7
通讯作者：
S. Yoshioka;K. Katayama;Chikako Okawa;Sachiko Takahashi;Satomi Tsukahara;J. Mitsuhashi;Y. Sugimoto
中科院分区：
文献类型：
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作者：
S. Yoshioka;K. Katayama;Chikako Okawa;Sachiko Takahashi;Satomi Tsukahara;J. Mitsuhashi;Y. Sugimoto
目的研究乳腺癌耐药蛋白中9个非同义生殖系突变/SNPs对乳腺癌发生的影响（BCRP/ABCG 2）基因对蛋白表达和功能的影响。（G151T，C458T，C496G，A616C，T623C，T742C，T1291C，A1768T，和G1858 ABCRP），并将它们在PA 317细胞中的外源表达效果与野生型对照进行比较。（T623 CBCRP-转染子）表达边缘水平的BCRP蛋白种类（65 kDa），其略小于野生型（70 kDa），但该突变体未出现在细胞表面或赋予耐药性。发现PA/F431 L细胞（T1291 CBCRP-转染子）表达70 kDa和65 kDa BCRP蛋白产物。此外，尽管PA/F431 L细胞表达的70 kDa BCRP水平与PA/WT细胞相当，但它们仅显示出对SN-38的轻微耐药性。PA/T153 M细胞（C458 TBCRP-转染子）和PA/D 620 N细胞（G1858 ABCRP-转染子）表达较低的BCRP量，并显示较低水平的耐药性SN-38相比PA/WT cells.ConclusionsWe已经表明，T623 CBCRP编码一个非功能性BCRP和T1291 CBCRP编码一个低功能性BCRP。因此，这些突变可能影响携带这些等位基因的患者中BCRP底物的药代动力学。
PurposeWe examined the effects of the nine nonsynonymous germ-line mutations/SNPs in thebreast cancer resistance protein (BCRP/ABCG2)gene on the expression and function of the protein.Materials and MethodsWe generated cDNAs for each of these mutants (G151T, C458T, C496G, A616C, T623C, T742C, T1291C, A1768T, and G1858ABCRP) and compared the effects of their exogenous expression in PA317 cells with a wild-type control.ResultsPA/F208S cells (T623CBCRP-transfectants) expressed marginal levels of a BCRP protein species (65kDa), which is slightly smaller than wild-type (70kDa), but this mutant did not appear on the cell surface or confer drug resistance. PA/F431L cells (T1291CBCRP-transfectants) were found to express both 70kDa and 65kDa BCRP protein products. In addition, although PA/F431L cells expressed 70kDa BCRP at comparable levels to PA/WT cells, they showed only marginal resistance to SN-38. PA/T153M cells (C458TBCRP-transfectants) and PA/D620N cells (G1858ABCRP-transfectants) expressed lower amounts of BCRP and showed lower levels of resistance to SN-38 compared with PA/WT cells.ConclusionsWe have shown that T623CBCRPencodes a non-functional BCRP and that T1291CBCRPencodes a low-functional BCRP. Hence, these mutations may affect the pharmacokinetics of BCRP substrates in patients harboring these alleles.