The CARMA3-Bcl10-MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor-Positive Breast Cancer.
The CARMA3-Bcl10-MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor-Positive Breast Cancer.
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DOI：
10.1158/0008-5472.can-17-1089
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发表时间：
2018-03-01
期刊：
影响因子：
11.2
通讯作者：
Lucas PC
中科院分区：
文献类型：
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作者：
Ekambaram P;Lee JL;Hubel NE;Hu D;Yerneni S;Campbell PG;Pollock N;Klei LR;Concel VJ;Delekta PC;Chinnaiyan AM;Tomlins SA;Rhodes DR;Priedigkeit N;Lee AV;Oesterreich S;McAllister-Lucas LM;Lucas PC
血管紧张素 II 受体 AGTR1 在血管疾病中介导血管收缩和炎症信号传导，在某些乳腺癌中异常过度表达。在这项研究中，我们确定了 AGTR1 响应性 NF-κB 信号通路在该乳腺癌亚型中的重要性。我们记录了 AGTR1 过表达发生在乳腺癌的管腔 A 和 B 亚型中，与 HER2 表达相互排斥，并与侵袭性特征相关，包括淋巴结转移增加、对新辅助治疗的反应性降低和总体生存率降低。从机制上讲，AGTR1 过表达引导 NF-κB 的配体依赖性和配体依赖性激活，这是由需要 CARMA3、Bcl10 和 MALT1（CBM 信号体）三联体的信号通路介导的。该通路的激活驱动癌细胞的内在反应，包括增殖、迁移和侵袭。此外，CBM 依赖性的 NF-κB 激活会引发癌细胞外在效应，影响肿瘤微环境的内皮细胞，促进肿瘤血管生成。因此，AGTR1+ 乳腺癌中的 CBM/NF-κB 信号传导通过多效性作用共同促进攻击行为。总体而言，我们的结果指出了在 HER2 阴性乳腺癌亚型中识别 AGTR1 过表达的预后和治疗价值，并且它们为探索重新利用靶向血管紧张素 II 依赖性 NF-κB 信号通路的药物以改善该乳腺癌亚型的治疗提供了机制原理。研究结果为探索重新利用靶向血管紧张素作用的药物以改善表达 AGTR1 的乳腺癌的治疗提供了机制原理。
The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NF-κB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NF-κB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell-intrinsic responses that include proliferation, migration and invasion. In addition, CBM-dependent activation of NF-κB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NF-κB signaling in AGTR1+ breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II-dependent NF-κB signaling pathways to improve the treatment of this breast cancer subset. Findings offer a mechanistic rationale to explore the repurposing of drugs that target angiotensin action to improve the treatment of AGTR1-expressing breast cancers.