Department of Dermatology, University of Colorado, Denver, Aurora, Colorado 80045, USA.
Mol Carcinog. 2012 Jun;51(6):500-7. doi: 10.1002/mc.20813. Epub 2011 Jun 16.
Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. Immunohistochemistry staining using human breast cancer tissue arrays revealed that 92% of invasive ductal breast cancer cases have CtBP1-positive staining compared to 4% CtBP1-positive in normal breast tissue. To explore the functional impact of CtBP1 in breast cancer, we examined CtBP1's transcriptional regulation of known tumor suppressors, breast cancer susceptibility gene 1 (Brca1), and E-cadherin. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. Concomitantly, Brca1 loss was detected in 57% and E-cadherin loss was detected in 76% of human invasive ductal breast cancers, and correlated with CtBP1 nuclear staining in these lesions. Importantly, siRNA knock down of CtBP1 restored Brca1 and E-cadherin expression in breast cancer cell lines, implying CtBP1 down-regulates Brca1 and E-cadherin genes in human breast cancer. This study provides evidence that although genetic loss of Brca1 and E-cadherin are infrequent in breast cancer, they are down-regulated at the transcriptional level by CtBP1 expression. Thus, CtBP1 activation could be a potential biomarker for breast cancer development.
羧基末端结合蛋白 1（CtBP1）是一种具有致癌潜能的转录共抑制因子。使用人类乳腺癌组织芯片进行免疫组织化学染色显示，92%的浸润性导管乳腺癌病例存在 CtBP1 阳性染色，而正常乳腺组织中只有 4%的 CtBP1 阳性染色。为了探究 CtBP1 在乳腺癌中的功能影响，我们研究了 CtBP1 对已知肿瘤抑制基因、乳腺癌易感基因 1（Brca1）和 E-钙黏蛋白的转录调控。我们发现 CtBP1 被招募到乳腺癌细胞中 Brca1 和 E-钙黏蛋白基因的启动子区域。同时，在 57%的人类浸润性导管乳腺癌中检测到 Brca1 缺失，在 76%的人类浸润性导管乳腺癌中检测到 E-钙黏蛋白缺失，并且与这些病变中的 CtBP1 核染色相关。重要的是，CtBP1 的 siRNA 敲低在乳腺癌细胞系中恢复了 Brca1 和 E-钙黏蛋白的表达，这表明 CtBP1 在人类乳腺癌中下调了 Brca1 和 E-钙黏蛋白基因的表达。本研究提供的证据表明，尽管在乳腺癌中 Brca1 和 E-钙黏蛋白的遗传缺失并不常见，但 CtBP1 的表达使其在转录水平下调。因此，CtBP1 的激活可能是乳腺癌发展的一个潜在生物标志物。
