C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance.
C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance.
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发表时间：
2002-06
影响因子：
5.7
通讯作者：
Y. Imai;M. Nakane;Kumie Kage;Satomi Tsukahara;E. Ishikawa;T. Tsuruo;Y. Miki;Y. Sugimoto
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作者：
Y. Imai;M. Nakane;Kumie Kage;Satomi Tsukahara;E. Ishikawa;T. Tsuruo;Y. Miki;Y. Sugimoto
乳腺癌耐药蛋白(BCRP)使癌细胞对诸如SN-38(伊立替康的活性代谢物)、米托蒽醌和拓扑替康等药物具有多药耐药性。在59个人肿瘤细胞系中，A549、NCI-H460、KM-12、HT-29、OVCAR-5和RPMI8226等6个细胞系显示高表达BCRP。从11个肿瘤细胞系中分离到BCRP基因，鉴定出3个突变的cDNA[G34A替代Val-12(V12M)，C421A替代GLN-141(Q141K)，以及缺失Ala-315和Thr-316的944-949缺失(delta315-6)]。G34A和C421A变异为多态，944-949缺失为剪接变异。与野生型BCRP表达水平相近的PA317细胞相比，C421A BCRP转染组PA317细胞的蛋白表达明显降低，且耐药水平较低。与野生型BCRP转染组相比，G34A或944-949缺失的BCRP转染组PA317细胞的蛋白表达和耐药性降低。在124名健康日本志愿者中，67人为野生型，48人为杂合子，9人为纯合子。提示部分人群具有C421A多态BCRP基因，并表达少量的Q141K BCRP。此外，在124例日本普通人群中，有3例发现GLN-126外显子4的C376T多态。这种C376T多态也可能有很高的影响，因为活性BCRP蛋白不会从C376T等位基因中表达出来。因此，携带C376T和/或C421A基因的人可能表达少量的BCRP，这种低表达可能导致正常细胞对伊立替康和米托蒽醌等抗癌药物的超敏反应。
Breast cancer resistance protein (BCRP) confers multidrug resistance to cancer cells against agents such as SN-38 (an active metabolite of irinotecan), mitoxantrone, and topotecan. Among 59 human tumor cell lines tested, 6 cell lines, A549, NCI-H460, KM-12, HT-29, OVCAR-5, and RPMI8226, showed high BCRP expression. BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln-141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (delta315-6)] were identified. G34A and C421A variants were polymorphisms, and 944-949 deletion was a splicing variant. C421A BCRP-transfected PA317 cells showed markedly decreased protein expression and low-level drug resistance compared with wild-type BCRP-transfected cells when transfectants expressed similar levels of BCRP mRNA. G34A or 944-949-deleted BCRP-transfected PA317 cells showed similar or somewhat lower protein expression and drug resistance compared with wild-type BCRP-transfected cells. Of 124 healthy Japanese volunteers, 67 were wild-type, 48 were heterozygous, and 9 were homozygous for the C421A allele. These results suggest that some people possess the C421A polymorphic BCRP gene and express low amounts of Q141K BCRP. In addition to that, C376T polymorphism in exon 4 substituting stop codon for Gln-126 was found in 3 of the 124 general Japanese population. This C376T polymorphism may also have high impact because active BCRP protein will not be expressed from the C376T allele. Therefore, people with C376T and/or C421A polymorphisms may express low amounts of BCRP, and this low BCRP expression might result in hypersensitivity of normal cells to such anticancer drugs as irinotecan and mitoxantrone.