BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen resistance in breast cancer cells
BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen resistance in breast cancer cells
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DOI：
10.1093/jnci/92.2.112
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发表时间：
2000-01-19
影响因子：
10.3
通讯作者：
Dorssers, LCJ
中科院分区：
文献类型：
--
作者：
Brinkman, A;van der Flier, S;Dorssers, LCJ
背景资料：用抗雌激素他莫昔芬治疗乳腺癌对大约一半的雌激素受体阳性患者有效，但由于对他莫昔芬耐药的转移瘤的发展，肿瘤经常复发。我们先前已经证明，通过插入缺陷型逆转录病毒基因组诱变人雌激素依赖性ZR-75-1乳腺癌细胞，导致细胞变得抗雌激素抗性。在这项研究中，我们分离并表征了乳腺癌抗雌激素抗性1（BCAR 1）位点的关键基因。方法/结果：通过细胞融合将BCAR 1基因座从逆转录病毒突变的抗雌激素抗性细胞转移到雌激素依赖性ZR-75-1细胞，赋予受体细胞抗雌激素抗性表型。通过使用外显子捕获和互补DNA（cDNA）文库筛选分离BCAR 1的完整编码序列，人BCAR 1 cDNA的序列分析预测了一个870个氨基酸的蛋白质，与大鼠p130 Cas-adapter蛋白高度同源。基因组分析显示，BCAR 1由7个外显子组成，位于染色体16q23.1。在多种人体组织中检测到BCAR 1转录物，其大小与逆转录病毒突变的ZR-75-1细胞产生的转录物相似。将BCAR 1 cDNA转染到ZR-75-1细胞中再次导致在抗雌激素存在下持续的细胞增殖，证实BCAR 1是该基因座中的负责基因。结论：BCAR 1基因过表达可使ZR-75-1乳腺癌细胞产生抗雌激素抵抗。BCAR 1在逆转录病毒突变细胞中的过表达似乎是由该基因启动子的激活引起的，该基因的分离和表征为阐明人类乳腺癌的生长变得不依赖于雌激素的机制开辟了新的途径。
Background: Treatment of breast cancer with the antiestrogen tamoxifen is effective in approximately one half of the patients with estrogen receptor-positive disease, but tumors recur frequently because of the development of metastases that are resistant to tamoxifen. We have previously shown that mutagenesis of human estrogen-dependent ZR-75-1 breast cancer cells by insertion of a defective retrovirus genome caused the cells to become antiestrogen resistant, In this study, we isolated and characterized the crucial gent at the breast cancer antiestrogen resistance 1 (BCAR1) locus. Methods/Results: Transfer of the BCAR1 locus from retrovirus-mutated, antiestrogen-resistant cells to estrogen-dependent ZR-75-1 cells by cell fusion conferred an antiestrogen-resistant phenotype on the recipient cells, The complete coding sequence of BCAR1 was isolated by use of exon-trapping and complementary DNA (cDNA) library screening, Sequence analysis of human BCAR1 cDNA predicted a protein of 870 amino acids that was strongly homologous to rat p130Cas-adapter protein. Genomic analysis revealed that BCAR1 consists of seven exons and is located at chromosome 16q23.1. BCAR1 transcripts were detected in multiple human tissues and were similar in size to transcripts produced by retrovirus-mutated ZR-75-1 cells. Transfection of BCAR1 cDNA into ZR-75-1 cells again resulted in sustained cell proliferation in the presence of antiestrogens, confirming that BCAR1 was the responsible gene in the locus. Conclusions: Overexpression of the BCAR1 gene confers antiestrogen resistance on human ZR-75-1 breast cancer cells. Overexpression of BCAR1 in retrovirus-mutated cells appears to result from activation of the gene's promoter, The isolation and characterization of this gene open new avenues to elucidating mechanisms by which the growth of human breast cancer becomes independent of estrogen.