Age-associated genes in human mammary gland drive human breast cancer progression
Age-associated genes in human mammary gland drive human breast cancer progression
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DOI：
10.1186/s13058-020-01299-2
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发表时间：
2020-06-15
影响因子：
7.4
通讯作者：
Sun, Lu-Zhe
中科院分区：
文献类型：
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作者：
Gu, Xiang;Wang, Bingzhi;Sun, Lu-Zhe
背景：衰老是乳腺癌的一种共病，提示衰老相关的转录组变化可能促进乳腺癌的进展。然而，年龄对乳腺癌影响的机制仍然知之甚少。方法我们分析了癌症基因组图谱（TCGA）数据集中82例乳腺癌患者的匹配正常乳腺组织的转录组学，并对与年龄相关表达的基因进行线性回归，这些基因与绝经无关。我们还分析了TCGA中成对肿瘤和非肿瘤乳腺组织之间的差异表达基因，以确定年龄和乳腺癌（ABC）相关基因。这些基因中的一些被选择用于进一步研究它们的恶性调节活性与体外和体内测定。结果在衰老过程中，我们鉴定了148个上调和189个下调的基因。正常组织和肿瘤组织中肿瘤相关基因与年龄依赖性基因的重叠导致了14个上调和24个下调的基因，这些基因与年龄和乳腺癌相关。这些基因预测无复发生存期，分别指示其潜在的肿瘤促进或抑制功能。敲低两个上调基因（DYNLT 3和P4HA 3）或过表达下调ALX 4显着降低乳腺癌细胞增殖，迁移和克隆形成。此外，P4HA3的敲低降低了小鼠中异种移植乳腺癌细胞的生长和转移，而ALX4的过表达抑制了异种移植乳腺癌细胞的生长。结论衰老过程中转录组的改变可能与乳腺肿瘤的发生有关。DYNLT3、P4HA3和ALX4在乳腺癌进展中发挥重要作用。
Background Aging is a comorbidity of breast cancer suggesting that aging-associated transcriptome changes may promote breast cancer progression. However, the mechanism underlying the age effect on breast cancer remains poorly understood. Method We analyzed transcriptomics of the matched normal breast tissues from the 82 breast cancer patients in The Cancer Genome Atlas (TCGA) dataset with linear regression for genes with age-associated expression that are not associated with menopause. We also analyzed differentially expressed genes between the paired tumor and non-tumor breast tissues in TCGA for the identification of age and breast cancer (ABC)-associated genes. A few of these genes were selected for further investigation of their malignancy-regulating activities with in vitro and in vivo assays. Results We identified 148 upregulated and 189 downregulated genes during aging. Overlapping of tumor-associated genes between normal and tumor tissues with age-dependent genes resulted in 14 upregulated and 24 downregulated genes that were both age and breast cancer associated. These genes are predictive in relapse-free survival, indicative of their potential tumor promoting or suppressive functions, respectively. Knockdown of two upregulated genes (DYNLT3 and P4HA3) or overexpression of the downregulated ALX4 significantly reduced breast cancer cell proliferation, migration, and clonogenicity. Moreover, knockdown of P4HA3 reduced growth and metastasis whereas overexpression of ALX4 inhibited the growth of xenografted breast cancer cells in mice. Conclusion Our study suggests that transcriptome alterations during aging may contribute to breast tumorigenesis. DYNLT3, P4HA3, and ALX4 play significant roles in breast cancer progression.