Nelson Nicholas, Jigo Raphael, Clark Geoffrey J
Department of Chemistry, US Naval Academy, Annapolis, MD 21402, USA.
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA.
Cancers (Basel). 2023 Aug 16;15(16):4133. doi: 10.3390/cancers15164133.
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.
BRCA1是一种具有复杂作用模式的肿瘤抑制因子。BRCA1的遗传性突变使携带者易患乳腺癌，而自发性乳腺癌通常在BRCA1表达方面存在缺陷。然而，BRCA1的单倍剂量不足或表达受抑制会导致DNA修复缺陷，进而引发DNA损伤反应，导致细胞衰老。Her2癌蛋白的激活突变或过表达也是乳腺癌常见的驱动因素。然而，通过RAS癌蛋白起作用的Her2过度激活也能诱导细胞衰老。据认为，此类肿瘤中p53和Rb肿瘤抑制机制必定还存在其他缺陷，以使细胞能够逃脱衰老，从而允许肿瘤发展。虽然BRCA1突变型乳腺癌通常为Her2阴性，但相当比例的Her2阳性肿瘤也会丧失BRCA1的表达。此类Her2+/BRCA1-肿瘤可能预期具有特别高的衰老障碍需要克服。一种重要的RAS衰老效应因子是蛋白NORE1A，它可调节p53和Rb。它是RAS癌蛋白必不可少的衰老效应因子，在乳腺肿瘤中常因启动子甲基化而下调。在此我们表明，NORE1A在复制叉停滞位点与BRCA1形成一种受Her2/RAS调节的内源性复合物。抑制NORE1A可阻断由BRCA1失活和Her2激活引起的衰老诱导。因此，NORE1A与BRCA1形成一种肿瘤抑制复合物。其频繁的表观遗传失活可能通过抑制衰老促进Her2+/BRCA1-介导的乳腺癌的转化。
