Department of Pathophysiology, College of Basic Medicine Science, China Medical University, Shenyang, Liaoning 110122, P.R. China.
Shenyang Maternity and Infant Hospital, Shenyang, Liaoning 110011, P.R. China.
Int J Oncol. 2018 Dec;53(6):2555-2565. doi: 10.3892/ijo.2018.4588. Epub 2018 Oct 9.
Breast cancer is one of the most frequently diagnosed types of cancer with a high mortality and malignancy rate in women worldwide. The Dickkopf (DKK) protein family, as a canonical Wnt/β-catenin pathway antagonist, has been implicated in both physiological and pathological processes. This study aimed to comprehensively characterize the prognostic value and elucidate the mechanisms of DKKs in breast cancer and its subtypes. Firstly, DKK mRNA expression and corresponding outcome were analyzed by means of the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) platform based on PAM50 intrinsic breast cancer subtypes. Subsequently, we extracted breast cancer datasets from the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to validate the expression profile and prognostic values from the GOBO platform. Moreover, a protein-protein network was created and functional enrichment was conducted to explore the underlying mechanisms of action of the DKKs. In addition, we uncovered the genetic and epigenetic alterations of DKK2 in breast cancer. The main finding of this study was the differential roles of DKKs in the PAM50 subtypes of breast cancer analyzed. The overall trend was that a high level of DKK2 was associated with a good survival in breast cancer, although it played an opposite role in the Normal-like subtype. We also found that DKK2 carried out its functions through multiple signaling pathways, not limited to the Wnt/β-catenin cascade in breast cancer. Finally, we used our own data to validate the bioinformatics analysis data for DKK2 by RT-qPCR. Taken together, our findings suggest that DKK2 may be a potential prognostic biomarker for the Normal-like subtype of breast cancer. However, the prognostic role of DKKs in the subtypes of breast cancer still requires validation by larger sample studies in the future.
乳腺癌是全球女性中最常见的癌症类型之一，死亡率和恶性程度较高。Dickkopf（DKK）蛋白家族作为经典的Wnt/β-catenin 通路拮抗剂，参与了生理和病理过程。本研究旨在全面描述 DKK 在乳腺癌及其亚型中的预后价值和作用机制。首先，我们利用基于 PAM50 内在乳腺癌亚型的基因表达预后在线（GOBO）平台分析了 DKK mRNA 表达及其相应的预后。随后，我们从癌症基因组图谱（TCGA）和乳腺癌国际分子分类联盟（METABRIC）中提取了乳腺癌数据集，以验证 GOBO 平台的表达谱和预后价值。此外，我们构建了蛋白质-蛋白质网络并进行了功能富集，以探索 DKK 作用的潜在机制。此外，我们揭示了 DKK2 在乳腺癌中的遗传和表观遗传改变。本研究的主要发现是分析的 PAM50 乳腺癌亚型中 DKKs 的不同作用。总体趋势是，高水平的 DKK2 与乳腺癌的良好生存相关，尽管在类似正常的亚型中起相反的作用。我们还发现 DKK2 通过多种信号通路发挥其功能，而不仅仅局限于乳腺癌中的 Wnt/β-catenin 级联。最后，我们使用自己的数据通过 RT-qPCR 验证了 DKK2 的生物信息学分析数据。总之，我们的研究结果表明，DKK2 可能是乳腺癌类似正常亚型的潜在预后生物标志物。然而，DKK 在乳腺癌亚型中的预后作用仍需要未来更大样本研究的验证。
