HER3 Differentiates Basal From Claudin Type Triple Negative Breast Cancer and Contributes to Drug and Microenvironmental Induced Resistance.
HER3 Differentiates Basal From Claudin Type Triple Negative Breast Cancer and Contributes to Drug and Microenvironmental Induced Resistance.
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DOI：
10.3389/fonc.2020.554704
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发表时间：
2020
影响因子：
4.7
通讯作者：
Mahmood U
中科院分区：
文献类型：
--
作者：
Sinevici N;Ataeinia B;Zehnder V;Lin K;Grove L;Heidari P;Mahmood U
三阴性乳腺癌（TNBC）是乳腺癌（BC）的一种侵袭性形式。靶向不同通路节点的许多激酶抑制剂（KI）在临床环境中显示出有限的获益。在这项研究中，我们的目的是表征HER 3依赖的程度，并确定Neuregulin（NRG）亚型在TNBC中的作用。在存在或不存在HER 3配体NRG的情况下，用一系列小分子抑制剂处理基底和紧密连接蛋白型TNBC细胞系。还通过AKT/MAPK信号传导途径的活力和生物化学评估在人癌细胞系中评价了单一药剂和组合疗法。我们显示，基底（BT 20、HCC-70和MDA-MB-468）和紧密连接蛋白型（MDA-MB-231、BT-549）TNBC细胞系显示出对HER受体家族的差异依赖。表达和动态HER 3上调在基础TNBC亚型中占主导地位。此外，天然配体NRG的存在显示出通过HER 3-AKT途径的有效信号传导，显著降低了所测试的AKT和PI 3 K抑制剂的功效。我们报告NRG增强了HER 3反馈机制，以使TNBC中的细胞持续存活。我们证明，有效阻断EGFR-HER 3-AKT通路的联合策略对于克服NRG依赖性和非依赖性耐药机制的代偿机制是必要的。我们的研究结果表明，EGFR-HER 3异二聚体形成了一个主要的信号传导枢纽，并且是基底型TNBC而不是Claudin型TNBC中肿瘤发生的关键参与者。因此，HER 3可以潜在地用作用于鉴定针对EGFR-HER 3-AKT轴的靶向治疗将最有价值的患者的生物标志物。
Triple Negative Breast Cancer (TNBC) is an aggressive form of Breast Cancer (BC). Numerous kinase inhibitors (KI) targeting different pathway nodes have shown limited benefit in the clinical setting. In this study, we aim to characterize the extent of HER3 reliance and to define the effect of Neuregulin (NRG) isoforms in TNBCs. Basal and Claudin type TNBC cell lines were treated with a range of small molecule inhibitors, in the presence or absence of the HER3 ligand NRG. Single agent and combination therapy was also evaluated in human cancer cell lines through viability and biochemical assessment of the AKT/MAPK signaling pathway. We show that Basal (BT20, HCC-70, and MDA-MB-468) and Claudin type (MDA-MB-231, BT-549) TNBC cell lines displayed differential reliance on the HER family of receptors. Expression and dynamic HER3 upregulation was predominant in the Basal TNBC subtype. Furthermore, the presence of the natural ligand NRG showed potent signaling through the HER3-AKT pathway, significantly diminishing the efficacy of the AKT and PI3K inhibitors tested. We report that NRG augments the HER3 feedback mechanism for continued cell survival in TNBC. We demonstrate that combination strategies to effectively block the EGFR-HER3-AKT pathway are necessary to overcome compensatory mechanisms to NRG dependent and independent resistance mechanisms. Our findings suggests that the EGFR-HER3 heterodimer forms a major signaling hub and is a key player in tumorigenesis in Basal but not Claudin type TNBC tested. Thus, HER3 could potentially serve as a biomarker for identifying patients in which targeted therapy against the EGFR-HER3-AKT axis would be most valuable.
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影响因子：
3.7
作者：
Schmukler E;Shai B;Ehrlich M;Pinkas-Kramarski R
通讯作者：
Pinkas-Kramarski R
影响因子：
17.1
作者：
Elkabets M;Vora S;Juric D;Morse N;Mino-Kenudson M;Muranen T;Tao J;Campos AB;Rodon J;Ibrahim YH;Serra V;Rodrik-Outmezguine V;Hazra S;Singh S;Kim P;Quadt C;Liu M;Huang A;Rosen N;Engelman JA;Scaltriti M;Baselga J
通讯作者：
Baselga J
影响因子：
--
作者：
Momeny M;Saunus JM;Marturana F;McCart Reed AE;Black D;Sala G;Iacobelli S;Holland JD;Yu D;Da Silva L;Simpson PT;Khanna KK;Chenevix-Trench G;Lakhani SR
通讯作者：
Lakhani SR
影响因子：
5.2
作者：
Liu, Chun-Yu;Chu, Pei-Yi;Tseng, Ling-Ming
通讯作者：
Tseng, Ling-Ming
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.