Wu Minhao, Soler David Ramos, Abba Martin C, Nunez Maria I, Baer Richard, Hatzis Christos, Llombart-Cussac Antonio, Llombart-Bosch Antonio, Aldaz C Marcelo
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park Research Division, 1808 Park Road 1C, P.O. Box 389, Smithville, TX 78957, USA.
Mol Cancer Res. 2007 Dec;5(12):1285-95. doi: 10.1158/1541-7786.MCR-07-0126.
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 CtIP, 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 CtIP 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 CtIP protein expression in a majority of ER+ breast cancer cell lines that we tested, but no or very little CtIP expression in ER-negative lines. Furthermore, CtIP protein expression status correlates with clinical response to neoadjuvant endocrine therapy, and patients with progressive disease express significantly lower CtIP protein in their primary breast carcinomas than those who respond. Meta-analysis of seven publicly available gene expression microarray data sets showed that CtIP expression is significantly associated with ER, disease-free survival, and breast cancer metastasis status. Importantly, we found that silencing endogenous CtIP in tamoxifen-sensitive breast cancer cells confers tamoxifen resistance. On the other hand, reexpression of CtIP in tamoxifen-resistant breast cancer cells restores sensitivity to the inhibitory growth effects of tamoxifen. Together, our findings indicate that CtIP silencing might be a novel mechanism for the development of tamoxifen resistance in breast cancer, suggesting that CtIP is likely associated with ER function, and that CtIP gene and protein expression may be useful biomarkers for breast cancer prognosis and clinical management.
获得性抗雌激素他莫昔芬耐药是乳腺癌治疗中的一个主要临床挑战。然而，其涉及的机制仍知之甚少。通过基因表达序列分析，我们鉴定出CtIP（一种与BRCA1和CtBP相互作用的蛋白）是雌激素受体α阳性（ER+）的MCF-7他莫昔芬耐药乳腺癌细胞中下调最显著的转录本之一。我们进一步在另一个ER+乳腺癌细胞系（T47D）中证实了CtIP下调与他莫昔芬耐药的关联，强化了所观察到现象的相关性。在其他研究中，我们发现在所检测的大多数ER+乳腺癌细胞系中有CtIP蛋白表达，但在ER阴性细胞系中没有或只有极少的CtIP表达。此外，CtIP蛋白表达状态与新辅助内分泌治疗的临床反应相关，疾病进展的患者其原发性乳腺癌中CtIP蛋白表达显著低于有反应的患者。对七个公开可用的基因表达微阵列数据集的荟萃分析表明，CtIP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，我们发现沉默他莫昔芬敏感乳腺癌细胞中的内源性CtIP可赋予他莫昔芬耐药性。另一方面，在他莫昔芬耐药乳腺癌细胞中重新表达CtIP可恢复对他莫昔芬抑制生长作用的敏感性。总之，我们的研究结果表明，CtIP沉默可能是乳腺癌中他莫昔芬耐药发生的一种新机制，提示CtIP可能与ER功能相关，并且CtIP基因和蛋白表达可能是乳腺癌预后和临床管理的有用生物标志物。
