文章：

BRCA1与NORE1A形成受Her2/Ras调控的肿瘤抑制复合体，调节细胞衰老过程

BRCA1 and NORE1A Form a Her2/Ras Regulated Tumor Suppressor Complex Modulating Senescence

原文发布日期：16 August 2023

DOI: 10.3390/cancers15164133

类型: Article

开放获取: 是

英文摘要：

BRCA1 is a tumor suppressor with a complex mode of action. Hereditary mutations in BRCA1 predispose carriers to breast cancer, and spontaneous breast cancers often exhibit defects in BRCA1 expression. However, haploinsufficiency or suppression of BRCA1 expression leads to defects in DNA repair, which can induce DNA damage responses, leading to senescence. Activating mutation or overexpression of the Her2 oncoprotein are also frequent drivers of breast cancer. Yet, over-activation of Her2, working through the RAS oncoprotein, can also induce senescence. It is thought that additional defects in the p53 and Rb tumor suppressor machinery must occur in such tumors to allow an escape from senescence, thus permitting tumor development. Although BRCA1 mutant breast cancers are usually Her2 negative, a significant percentage of Her2 positive tumors also lose their expression of BRCA1. Such Her2+/BRCA1− tumors might be expected to have a particularly high senescence barrier to overcome. An important RAS senescence effector is the protein NORE1A, which can modulate both p53 and Rb. It is an essential senescence effector of the RAS oncoprotein, and it is often downregulated in breast tumors by promotor methylation. Here we show that NORE1A forms a Her2/RAS regulated, endogenous complex with BRCA1 at sites of replication fork arrest. Suppression of NORE1A blocks senescence induction caused by BRCA1 inactivation and Her2 activation. Thus, NORE1A forms a tumor suppressor complex with BRCA1. Its frequent epigenetic inactivation may facilitate the transformation of Her2+/BRCA1− mediated breast cancer by suppressing senescence.

摘要翻译： 

BRCA1是一种具有复杂作用模式的肿瘤抑制因子。遗传性BRCA1突变使携带者易患乳腺癌，且自发性乳腺癌常表现出BRCA1表达缺陷。然而，BRCA1单倍体不足或表达抑制会导致DNA修复缺陷，从而诱发DNA损伤反应并导致细胞衰老。Her2癌蛋白的激活突变或过表达同样是乳腺癌的常见驱动因素，但通过RAS癌蛋白介导的Her2过度激活亦可诱导衰老。学界认为此类肿瘤必须伴随p53和Rb肿瘤抑制机制的额外缺陷，才能逃逸衰老进程从而促进肿瘤发展。虽然BRCA1突变型乳腺癌通常呈Her2阴性，但相当比例的Her2阳性肿瘤同样存在BRCA1表达缺失。这类Her2阳性/BRCA1阴性肿瘤可能需要克服尤为显著的衰老屏障。RAS重要的衰老效应蛋白NORE1A能够同时调控p53和Rb，它是RAS癌蛋白不可或缺的衰老效应因子，但在乳腺肿瘤中常因启动子甲基化而下调。本研究表明，在复制叉停滞位点，NORE1A与BRCA1形成受Her2/RAS调控的内源性复合体。抑制NORE1A可阻断由BRCA1失活和Her2激活引发的衰老诱导。因此，NORE1A与BRCA1共同构成肿瘤抑制复合体，其频繁表现遗传失活可能通过抑制衰老促进Her2阳性/BRCA1阴性介导的乳腺癌转化。

原文链接：

BRCA1 and NORE1A Form a Her2/Ras Regulated Tumor Suppressor Complex Modulating Senescence