Cell Biology Unit, Department of Pathology, Landspitali-The National University Hospital of Iceland, 101 Reykjavik, Iceland.
BMC (Biomedical Center), Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
Genes (Basel). 2023 Jul 29;14(8):1559. doi: 10.3390/genes14081559.
The disruption of endoplasmic reticulum (ER) homeostasis occurs in many human diseases. Atlastins (ATLs) maintain the branched network of the ER. The dysregulation of ATL2, located at ER network junctions, has been associated with cancer. ATL2 is necessary for lipid droplet formation in murine breast tissue. Thus, we analyzed whether ATL2 has a role in human breast cancer (BC) pathology. The expression of ATL2 variant ATL2-2 was analyzed in breast tumors from the BC cohorts of the TCGA, METABRIC, and two independent Icelandic cohorts, Cohort 1 and 2; its association with clinical, pathological, survival, and cellular pathways was explored. ATL2-2 mRNA and protein expression were higher in breast tumors than in normal tissue. ATL2-2 mRNA associated with tumor characteristics that indicate a worse prognosis. In METABRIC, high ATL2-2 mRNA levels were associated with shorter BC-specific survival (BCSS) in patients with estrogen-receptor-positive luminal breast tumors, which remained significant after correction for grade and tumor size (HR 1.334, CI 1.063-1.673). Tumors with high ATL2 mRNA showed an upregulation of hallmark pathways MYC targets v1, E2F targets, and G2M checkpoint genes. Taken together, the results suggest that high levels of ATL2-2 may support BC progression through key cancer driver pathways.
内质网 (ER) 稳态的破坏发生在许多人类疾病中。Atlastins (ATLs) 维持 ER 的分支网络。位于 ER 网络连接处的 ATL2 的失调与癌症有关。ATL2 是小鼠乳腺组织中脂滴形成所必需的。因此，我们分析了 ATL2 是否在人类乳腺癌 (BC) 病理学中发挥作用。我们分析了 TCGA、METABRIC 和两个独立的冰岛队列（队列 1 和 2）的 BC 队列中乳腺癌肿瘤中的 ATL2 变体 ATL2-2 的表达；探索了其与临床、病理、生存和细胞途径的关联。与正常组织相比，乳腺癌肿瘤中 ATL2-2 mRNA 和蛋白表达水平更高。ATL2-2 mRNA 与提示预后不良的肿瘤特征相关。在 METABRIC 中，高 ATL2-2 mRNA 水平与雌激素受体阳性腔型乳腺癌患者的 BC 特异性生存 (BCSS) 较短相关，在经过分级和肿瘤大小校正后仍然显著 (HR 1.334, CI 1.063-1.673)。高 ATL2 mRNA 的肿瘤表现出标志性途径 MYC 靶标 v1、E2F 靶标和 G2M 检查点基因的上调。综上所述，结果表明，高水平的 ATL2-2 可能通过关键的癌症驱动途径支持 BC 的进展。
