Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches.
Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches.
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DOI：
10.1158/0008-5472.can-07-5744
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Miele L
中科院分区：
文献类型：
--
作者：
Rizzo P;Miao H;D'Souza G;Osipo C;Song LL;Yun J;Zhao H;Mascarenhas J;Wyatt D;Antico G;Hao L;Yao K;Rajan P;Hicks C;Siziopikou K;Selvaggi S;Bashir A;Bhandari D;Marchese A;Lendahl U;Qin JZ;Tonetti DA;Albain K;Nickoloff BJ;Miele L
Notch-1 和 Jagged-1 mRNA 的高表达与乳腺癌的不良预后相关。阐明 Notch 和其他主要乳腺癌途径之间的相互作用对于确定哪些患者可能受益于 Notch 抑制剂、哪些药物应与其联合使用以及哪些生物标志物表明 Notch 体内活性至关重要。我们利用细胞系和异种移植物探索了临床样本中 Notch 受体和配体的表达，以及 Notch 信号传导的活性、调节和效应器。导管癌和小叶癌通常以不同水平表达 Notch-1、Notch-4 和 Jagged-1。然而，在乳腺癌细胞系中，Notch 诱导的转录活性与 Notch 受体水平无关，并且在雌激素受体 α 阴性 (ERα-)、Her2/Neu 非过表达细胞中最高。在 ERα+ 细胞中，雌二醇抑制 Notch 活性和 Notch-1IC 核水平，并影响 Notch-1 细胞分布。他莫昔芬和雷洛昔芬阻断了这种效应，重新激活了Notch。 Notch-1 诱导 Notch-4。临床标本中的 Notch-4 表达与增殖相关 (Ki67)。在 MDA-MB231 (ERα–) 细胞中，Notch-1 敲低或 γ-分泌酶抑制会降低细胞周期蛋白 A 和 B1，导致 G2 停滞、不依赖于 p53 的 NOXA 诱导和死亡。在 T47D:A18 (ERα+) 细胞中，相同的靶点受到影响，Notch 抑制增强了他莫昔芬的作用。在体内，γ-分泌酶抑制剂治疗可抑制 MDA-MB231 肿瘤的生长，并与他莫昔芬联合使用，引起 T47D:A18 肿瘤的消退。我们的数据表明，抗雌激素和Notch抑制剂的组合可能对ERα+乳腺癌有效，而Notch信号传导是ERα-乳腺癌的潜在治疗靶点。
High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor α–negative (ERα–), Her2/Neu nonoverexpressing cells. In ERα+ cells, estradiol inhibited Notch activity and Notch-1IC nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ERα–) cells, Notch-1 knockdown or γ-secretase inhibition decreased cyclins A and B1, causing G2 arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERα+) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, γ;-secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERα+ breast cancers and that Notch signaling is a potential therapeutic target in ERα– breast cancers.