Breast cancer, which is the most common type of cancer among women, is a heterogenous disease. It results from progressive accumulation of genetic and epigenetic alterations in different genes. The Dok1 protein has been identified as the major substrate of protein tyrosine kinases in hematopoietic cells. It is considered as a tumor suppressor due to the reports which describe its inhibitory effect on major oncogenic signaling pathways such as Mek/Erk/PI3k/Akt and Wnt/β-catenin. In this study, we investigated the mutation frequency of the DOK1 gene in 118 breast tumors using Sanger sequencing and DOK1 mRNA expression level in 63 breast cancer samples using qRT-PCR methods. Although the mutation frequency was low DOK1 mRNA expression levels were significantly reduced (63.5%) in the tumors compared to adjacent non-cancerous tissue. We also correlated expression changes with clinicopathological characteristics. Low mRNA levels correlated with age (p = 0.01) and c-erbB-2 (p = 0.05). In most of the previous reports, down-regulation of DOK1 mRNA expression has been associated with promoter methylation. We identified four different coding sequence alterations in 5.1% (6/118) of the tumor samples. However, all of these alterations were located in the functional domains of the protein. Therefore, these mutations may affect the function and/or cellular localization of the protein and contribute to cancer progression by this way. In conclusion our data indicate that DOK1 acts as a tumor suppressor in breast cancer and association of Dok1 with the c-erbB-2 mediated mechanism of action in breast cancer needs to be investigated.

中文翻译：

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乳腺癌中DOK1基因的分析。

乳腺癌是女性中最常见的癌症，是一种异质性疾病。它是由于不同基因中遗传和表观遗传变化的逐步积累而产生的。Dok1蛋白已被鉴定为造血细胞中蛋白酪氨酸激酶的主要底物。由于其描述了其对主要致癌信号传导途径如Mek / Erk / PI3k / Akt和Wnt /β-catenin的抑制作用的报道，因此将其视为肿瘤抑制剂。在这项研究中，我们使用Sanger测序研究了118个乳腺肿瘤中DOK1基因的突变频率，并使用qRT-PCR方法研究了63个乳腺癌样品中DOK1 mRNA的表达水平。尽管突变频率较低，但与相邻的非癌性组织相比，DOK1 mRNA的表达水平在肿瘤中明显降低（63.5％）。我们还将表达变化与临床病理特征相关联。低mRNA水平与年龄（p = 0.01）和c-erbB-2（p = 0.05）相关。在大多数以前的报告中，DOK1 mRNA表达的下调与启动子甲基化有关。我们在5.1％（6/118）的肿瘤样本中鉴定出四种不同的编码序列改变。但是，所有这些改变都位于蛋白质的功能域中。因此，这些突变可能会影响蛋白质的功能和/或细胞定位，并通过这种方式促进癌症的进展。总而言之，我们的数据表明DOK1在乳腺癌中起着抑癌作用，Dok1与c-erbB-2介导的乳腺癌作用机制的相关性需要进行研究。