Laboratory of General Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Cardiothoracic Surgery, Xiamen University Affiliated Southeast Hospital, Zhangzhou, China.
Mol Oncol. 2017 Dec;11(12):1752-1767. doi: 10.1002/1878-0261.12141. Epub 2017 Oct 27.
TFIIB-related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase-dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha (ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER-positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its siRNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease.
TFIIB 相关因子 1（Brf1）调节 RNA Pol III 基因（聚合酶依赖性基因）的转录。Pol III 基因的上调增强了 tRNA 和 5S RNA 的产生，并增加了细胞的翻译能力，从而促进细胞转化和肿瘤发展。然而，Brf1 在人乳腺癌（HBC）中的过表达意义仍有待研究。在这里，我们研究了 HBC 样本中 Brf1 的表达是否增加，并探讨了其分子机制以及 Brf1 在 HBC 中的表达意义。收集了 218 例 HBC 样本，通过细胞学和分子生物学方法确定 Brf1 的表达。我们利用共定位、共免疫沉淀和染色质免疫沉淀方法来研究 Brf1 与雌激素受体 alpha（ERα）的相互作用。我们确定了 Brf1 和 ERα 如何调节 Pol III 基因。结果表明，Brf1 在大多数 HBC 病例中过表达，这与 ER 阳性状态有关。激素治疗后，高 Brf1 表达组的病例生存期明显长于低 Brf1 表达组。ERα 介导 Brf1 的表达。Brf1 和 ERα 在核内共定位。这些结果表明 Brf1 与 ERα 之间存在相互作用，协同调节 Pol III 基因的转录。用其 siRNA 或他莫昔芬抑制 ERα 可降低乳腺癌细胞中 Brf1 和 Pol III 基因表达水平，并降低乳腺癌细胞集落形成率。总之，这些研究表明 Brf1 是 HBC 诊断和预后的良好生物标志物。Brf1 与 ERα 的这种相互作用以及 Brf1 本身是该疾病的潜在治疗靶点。
