Department of Anesthesiology, Harbin Medical University Cancer Hospital, Haping Road No. 150, Harbin, 150081, Heilongjiang, China.
Department of Medical Records, Harbin Medical University Cancer Hospital, Haping Road No. 150, Harbin, 150081, Heilongjiang, China.
Sci Rep. 2024 Mar 21;14(1):6769. doi: 10.1038/s41598-024-57189-6.
Breast cancer is a serious threat to human health. The transforming growth factor-β signaling pathway is an important pathway involved in the occurrence and development of cancer. The SMAD family genes are responsible for the TGF-β signaling pathway. However, the mechanism by which genes of the SMAD family are involved in breast cancer is still unclear. Therefore, it is necessary to investigate the biological roles of the SMAD family genes in breast cancer. We downloaded the gene expression data, gene mutation data, and clinical pathological data of breast cancer patients from the UCSC Xena database. We used the Wilcox test to estimate the expression of genes of the SMAD family in cancers. And the biological functions of SMAD family genes using the DAVID website. The Pearson correlation method was used to explore the immune cell infiltration and drug response of SMAD family genes. We conducted in biological experiments vitro and vivo. In this study, we integrated the multi-omics data from TCGA breast cancer patients for analysis. The expression of genes of SMAD family was significantly dysregulated in patients with breast cancer. Except for SMAD6, the expression of other SMAD family genes was positively correlated. We also found that genes of the SMAD family were significantly enriched in the TGF-β signaling pathway, Hippo signaling pathway, cell cycle, and cancer-related pathways. In addition, SMAD3, SMAD6, and SMAD7 were lowly expressed in stage II breast cancer, while SMAD4 and SMAD2 were lowly expressed in stage III cancer. Furthermore, the expression of genes of the SMAD family was significantly correlated with immune cell infiltration scores. Constructing a xenograft tumor mouse model, we found that SMAD3 knockdown significantly inhibited tumorigenesis. Finally, we analyzed the association between these genes and the IC50 value of drugs. Interestingly, patients with high expression of SMAD3 exhibited significant resistance to dasatinib and staurosporine, while high sensitivity to tamoxifen and auranofin. In addition, SMAD3 knockdown promoted the apoptosis of BT-549 cells and decreased cell activity, and BAY-1161909 and XK-469 increased drug efficacy. In conclusion, genes of the SMAD family play a crucial role in the development of breast cancer.
乳腺癌是严重威胁人类健康的疾病。转化生长因子-β（TGF-β）信号通路是癌症发生发展过程中的重要通路，SMAD 家族基因负责 TGF-β信号通路。然而，SMAD 家族基因在乳腺癌中的作用机制尚不清楚。因此，有必要研究 SMAD 家族基因在乳腺癌中的生物学作用。我们从 UCSC Xena 数据库下载了乳腺癌患者的基因表达数据、基因突变数据和临床病理数据。我们使用 Wilcox 检验估计 SMAD 家族基因在癌症中的表达。并使用 DAVID 网站研究 SMAD 家族基因的生物学功能。使用 Pearson 相关法探索 SMAD 家族基因的免疫细胞浸润和药物反应。我们进行了体外和体内的生物学实验。在这项研究中，我们整合了 TCGA 乳腺癌患者的多组学数据进行分析。乳腺癌患者的 SMAD 家族基因表达明显失调。除了 SMAD6，其他 SMAD 家族基因的表达呈正相关。我们还发现，SMAD 家族基因在 TGF-β 信号通路、Hippo 信号通路、细胞周期和癌症相关通路中显著富集。此外，SMAD3、SMAD6 和 SMAD7 在 II 期乳腺癌中低表达，而 SMAD4 和 SMAD2 在 III 期癌症中低表达。此外，SMAD 家族基因的表达与免疫细胞浸润评分显著相关。构建异种移植肿瘤小鼠模型，我们发现 SMAD3 敲低显著抑制肿瘤发生。最后，我们分析了这些基因与药物 IC50 值之间的关联。有趣的是，SMAD3 高表达的患者对 dasatinib 和 staurosporine 表现出显著的耐药性，而对 tamoxifen 和 auranofin 则表现出高度敏感性。此外，SMAD3 敲低促进 BT-549 细胞凋亡并降低细胞活性，BAY-1161909 和 XK-469 增加药物疗效。总之，SMAD 家族基因在乳腺癌的发生发展中起着至关重要的作用。
