The Ras-related gene ERAS is involved in human and murine breast cancer.
The Ras-related gene ERAS is involved in human and murine breast cancer.
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DOI：
10.1038/s41598-018-31326-4
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发表时间：
2018-08-29
影响因子：
4.6
通讯作者：
Navarro M
中科院分区：
文献类型：
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作者：
Suárez-Cabrera C;de la Peña B;González LL;Page A;Martínez-Fernández M;Casanova ML;Paramio JM;Rojo-Sebastián A;Moreno-Bueno G;Maroto A;Ramírez Á;Navarro M
虽然Ras基因在人类肿瘤中经常发生突变，但这些突变在乳腺癌中并不常见。然而，许多乳腺肿瘤显示Ras通路激活的证据。在这篇文章中，我们分析和表征了随机睡美人转座子诱变产生的小鼠乳腺肿瘤，并确定ERAS -成人组织中沉默的RAS家族成员-作为一个新的基因参与乳腺癌的进展和恶性。ERAS在人非转化乳腺细胞中的强制表达诱导上皮向间充质转化的过程和干细胞标志物的增加;这些变化由miR-200 c下调介导。ERAS在人致瘤性乳腺细胞中的表达导致异种移植实验中产生更大和分化程度更低的肿瘤。对人类样本的免疫组织化学、RT-qPCR和生物信息学分析显示，ERAS在8-10%的乳腺肿瘤中异常表达，并且这种表达与远处转移和降低的无转移生存率相关。总之，我们的研究结果表明，不适当的激活ERAS可能是重要的一个子集的乳腺肿瘤的发展。这些发现为ERAS表达肿瘤的这一子集开辟了新的特异性治疗的可能性。
Although Ras genes are frequently mutated in human tumors, these mutations are uncommon in breast cancer. However, many breast tumors show evidences of Ras pathway activation. In this manuscript, we have analyzed and characterized mouse mammary tumors generated by random Sleeping Beauty transposon mutagenesis and identify ERAS -a member of the RAS family silenced in adult tissues- as a new gene involved in progression and malignancy of breast cancer. Forced expression of ERAS in human non-transformed mammary gland cells induces a process of epithelial-to-mesenchymal transition and an increase in stem cells markers; these changes are mediated by miR-200c downregulation. ERAS expression in human tumorigenic mammary cells leads to the generation of larger and less differentiated tumors in xenotransplant experiments. Immunohistochemical, RT-qPCR and bioinformatics analysis of human samples show that ERAS is aberrantly expressed in 8–10% of breast tumors and this expression is associated with distant metastasis and reduced metastasis-free survival. In summary, our results reveal that inappropriate activation of ERAS may be important in the development of a subset of breast tumors. These findings open the possibility of new specific treatments for this subset of ERAS-expressing tumors.