BRCA1 and NORE1A Form a Her2/Ras Regulated Tumor Suppressor Complex Modulating Senescence.
BRCA1 and NORE1A Form a Her2/Ras Regulated Tumor Suppressor Complex Modulating Senescence.
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DOI：
10.3390/cancers15164133
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发表时间：
2023-08-16
期刊：
影响因子：
5.2
通讯作者：
Clark, Geoffrey J.
中科院分区：
文献类型：
--
作者：
Nelson, Nicholas;Jigo, Raphael;Clark, Geoffrey J.
BRCA 1肿瘤抑制因子的功能丧失在乳腺癌中很常见，但在实验中，BRCA 1失活会促进细胞衰老。通过Her 2上调过度刺激RAS信号传导在乳腺癌中也很常见，但它也可能导致衰老。相当大比例的原发性乳腺肿瘤表现出这两种缺陷。那么，它们是如何克服衰老反应成为成功的肿瘤的呢？在这里，我们表明RAS衰老效应NORE 1A可以与BRCA 1复合，NORE 1A的缺失消除了Her 2和BRCA 1失调的衰老诱导作用。数据库分析显示，NORE 1A表达缺失在原发性乳腺肿瘤中很常见，并且与Her 2+而非Her 2 −病例中的BRCA 1缺失相关。BRCA 1是一种具有复杂作用模式的肿瘤抑制因子。BRCA 1基因的遗传性突变使携带者易患乳腺癌，自发性乳腺癌通常表现出BRCA 1表达的缺陷。然而，单倍不足或BRCA 1表达的抑制导致DNA修复缺陷，这可以诱导DNA损伤反应，导致衰老。Her 2癌蛋白的激活突变或过表达也是乳腺癌的常见驱动因素。然而，Her 2的过度激活，通过RAS癌蛋白起作用，也可以诱导衰老。据认为，在p53和Rb肿瘤抑制机制中的额外缺陷必须发生在这样的肿瘤中，以允许逃避衰老，从而允许肿瘤发展。虽然BRCA 1突变型乳腺癌通常是Her 2阴性的，但相当大比例的Her 2阳性肿瘤也失去了BRCA 1的表达。这种Her 2 +/BRCA 1 −肿瘤可能需要克服特别高的衰老障碍。一个重要的RAS衰老效应子是蛋白质NORE 1A，它可以调节p53和Rb。它是RAS癌蛋白的重要衰老效应子，在乳腺肿瘤中常通过启动子甲基化下调。在这里，我们表明，NORE 1A形成Her 2/RAS调节，内源性复合物与BRCA 1在复制叉停滞的网站。NORE 1A的抑制阻断了由BRCA 1失活和Her 2激活引起的衰老诱导。因此，NORE 1A与BRCA 1形成肿瘤抑制复合物。其频繁的表观遗传失活可能通过抑制衰老促进Her 2 +/BRCA 1 −介导的乳腺癌的转化。
The loss of function of the BRCA1 tumor suppressor is common in breast cancer, but experimentally, the BRCA1 inactivation promotes cell senescence. The overstimulation of RAS signaling via Her2 upregulation is also common in breast cancer, yet it can also lead to senescence. A significant percent of primary breast tumors exhibit both defects. So how do they overcome the senescence response to become successful tumors? Here we show that the RAS senescence effector NORE1A can complex with BRCA1 and that loss of NORE1A abrogates the senescence-inducing effects of Her2 and BRCA1 dysregulation. Database analysis shows that NORE1A loss of expression is common in primary breast tumors and correlates with BRCA1 loss in Her2+ but not Her2− cases. 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.
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影响因子：
56.9
作者：
FUTREAL, PA;LIU, QY;WISEMAN, R
通讯作者：
WISEMAN, R
影响因子：
4.8
作者：
Barnoud, Thibaut;Donninger, Howard;Clark, Geoffrey J.
通讯作者：
Clark, Geoffrey J.
影响因子：
28.2
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ
癌基因诱导的DNA损伤反应与衰老和癌症异染色质之间的相互作用。
影响因子：
21.3
作者：
Di Micco R;Sulli G;Dobreva M;Liontos M;Botrugno OA;Gargiulo G;dal Zuffo R;Matti V;d'Ario G;Montani E;Mercurio C;Hahn WC;Gorgoulis V;Minucci S;d'Adda di Fagagna F
通讯作者：
d'Adda di Fagagna F
影响因子：
9.7
作者：
Barnoud T;Schmidt ML;Donninger H;Clark GJ
通讯作者：
Clark GJ