Garcia Vanesa, Domínguez Gemma, García José M, Silva Javier, Peña Cristina, Silva José M, Carcereny Enric, Menendez Josefa, España Pilar, Bonilla Félix
Department of Medical Oncology, Hospital Universitario Puerta de Hierro, E-28035 Madrid, Spain.
J Pathol. 2004 Feb;202(2):224-32. doi: 10.1002/path.1513.
The ZBRK1 protein is a member of the KRAB-ZFP family. It functions as a transcriptional repressor by binding to its recognition sequence within target genes and producing a nucleoprotein complex containing its co-repressor BRCA1 and also probably the co-repressor KAP-1. Alterations that affect the ZBRK1 gene have not been reported in human tumours. For this reason, possible alterations in the ZBRK1 gene have been studied by analysing mRNA expression using real-time polymerase chain reaction (PCR), and gene sequence using single strand conformation polymorphism (SSCP) analysis and DNA sequencing, in 61 patients with primary breast carcinomas. BRCA1 mRNA expression and allelic loss were also studied in 25 of the same patients. ZBRK1 was underexpressed in 28 (45.9%) and overexpressed in 18 (29.5%) of the 61 cases. No significant association was observed between ZBRK1 mRNA expression and clinicopathological parameters. Loss of heterozygosity of the BRCA1 gene was found in 3 of 23 (13%) informative cases and BRCA1 mRNA expression was altered in 11 of 25 (44%) cases. No significant correlation was found between altered BRCA1 expression and the different types of ZBRK1 mRNA expression. Nine polymorphisms were found in the ZBRK1 sequence, with no significant differences between patients and control subjects. Altered ZBRK1 expression correlated significantly with two of these polymorphisms. A point mutation in one polymorphism and allelic loss in one patient were also observed, findings that indicate that these inactivation mechanisms do not frequently affect this gene. Altered expression of the ZBRK1 gene is therefore frequent in primary breast carcinoma. The functional significance of the polymorphisms in this gene is unclear.
ZBRK1蛋白是KRAB-ZFP家族的成员。它通过与靶基因内的识别序列结合并产生一种核蛋白复合物来发挥转录抑制因子的作用，该核蛋白复合物包含其共抑制因子BRCA1，可能还包含共抑制因子KAP-1。尚未在人类肿瘤中报道影响ZBRK1基因的改变。因此，通过使用实时聚合酶链反应（PCR）分析mRNA表达，以及使用单链构象多态性（SSCP）分析和DNA测序来研究ZBRK1基因的可能改变，研究对象为61例原发性乳腺癌患者。还对其中25例相同患者的BRCA1 mRNA表达和等位基因缺失进行了研究。在61例病例中，28例（45.9%）ZBRK1表达下调，18例（29.5%）ZBRK1表达上调。未观察到ZBRK1 mRNA表达与临床病理参数之间存在显著关联。在23例信息充分的病例中有3例（13%）发现BRCA1基因杂合性缺失，在25例病例中有11例（44%）BRCA1 mRNA表达发生改变。未发现BRCA1表达改变与不同类型的ZBRK1 mRNA表达之间存在显著相关性。在ZBRK1序列中发现了9个多态性位点，患者与对照受试者之间无显著差异。ZBRK1表达改变与其中两个多态性位点显著相关。还观察到一个多态性位点存在点突变，一名患者存在等位基因缺失，这些结果表明这些失活机制并不经常影响该基因。因此，ZBRK1基因表达改变在原发性乳腺癌中很常见。该基因多态性的功能意义尚不清楚。
