CUP silencing as a novel mechanism of tamoxifen resistance in breast cancer
CUP silencing as a novel mechanism of tamoxifen resistance in breast cancer
复制标题
DOI：
10.1158/1541-7786.mcr-07-0126
复制
发表时间：
2007-12-01
影响因子：
5.2
通讯作者：
Aldaz, C. Marcelo
中科院分区：
文献类型：
--
作者：
Wu, Minhao;Soler, David Ramos;Aldaz, C. Marcelo
对抗雌激素药物他莫昔芬的获得性耐药构成了乳腺癌治疗的主要临床挑战。然而，人们对其中涉及的机制仍知之甚少。通过基因表达的系列分析，我们发现了BRCA1和CtBP相互作用的蛋白CUP是雌激素受体α阳性(ER+)MCF-7三苯氧胺耐药乳腺癌细胞中最显著下调的转录本之一。我们进一步证实，在另一个ER+乳腺癌株(T47D)中，CUP下调与他莫昔芬耐药有关，从而加强了观察到的现象的相关性。在其他研究中，我们发现在我们测试的大多数ER+乳腺癌细胞系中都有CUP蛋白的表达，但在ER阴性的乳腺癌细胞系中没有或很少表达CUP蛋白。此外，CUP蛋白的表达状态与新辅助内分泌治疗的临床疗效相关，进展性疾病患者的原发乳腺癌中CUP蛋白的表达明显低于有反应的患者。对7个公开可用的基因表达微阵列数据集的荟萃分析表明，CUP的表达与ER、无病生存期和乳腺癌转移状态显著相关。重要的是，我们发现沉默对他莫昔芬敏感的乳腺癌细胞中的内源性CUP会增加他莫昔芬的耐药性。另一方面，在对他莫昔芬耐药的乳腺癌细胞中重新表达CUP，恢复了对他莫昔芬抑制生长效应的敏感性。总之，我们的研究结果表明，CUP沉默可能是乳腺癌三苯氧胺耐药形成的一种新机制，提示CUP可能与ER功能有关，CUP基因和蛋白的表达可能是乳腺癌预后和临床治疗的有用生物标志物。
Acquired resistance to the antiestrogen tamoxifen constitutes a major clinical challenge in breast cancer therapy. However, the mechanisms involved are still poorly understood. Using serial analysis of gene expression, we identified CUP, a BRCA1- and CtBP-interacting protein, as one of the most significantly down-regulated transcripts in estrogen receptor alpha-positive (ER+) MCF-7 tamoxifen-resistant breast cancer cells. We further confirmed the association of CUP down-regulation with tamoxifen resistance in an additional ER+ breast cancer line (T47D), strengthening the relevance of the phenomenon observed. In additional studies, we found CUP protein expression in a majority of ER+ breast cancer cell lines that we tested, but no or very little CUP expression in ER-negative lines. Furthermore, CUP protein expression status correlates with clinical response to neoadjuvant endocrine therapy, and patients with progressive disease express significantly lower CUP protein in their primary breast carcinomas than those who respond. Meta-analysis of seven publicly available gene expression microarray data sets showed that CUP expression is significantly associated with ER, disease-free survival, and breast cancer metastasis status. Importantly, we found that silencing endogenous CUP in tamoxifen-sensitive breast cancer cells confers tamoxifen resistance. On the other hand, reexpression of CUP in tamoxifen-resistant breast cancer cells restores sensitivity to the inhibitory growth effects of tamoxifen. Together, our findings indicate that CUP silencing might be a novel mechanism for the development of tamoxifen resistance in breast cancer, suggesting that CUP is likely associated with ER function, and that CUP gene and protein expression may be useful biomarkers for breast cancer prognosis and clinical management.