Targeting TACE-dependent EGFR ligand shedding in breast cancer
Targeting TACE-dependent EGFR ligand shedding in breast cancer
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DOI：
10.1172/jci29518
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发表时间：
2007-02-01
影响因子：
15.9
通讯作者：
Bissell, Mina J.
中科院分区：
文献类型：
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作者：
Kenny, Paraic A.;Bissell, Mina J.
独立于其他细胞类型的信号而增殖的能力是肿瘤细胞的基本特征。使用人类乳腺癌进展的3D培养模型，我们描绘了蛋白酶依赖的自分泌环，在没有原癌基因突变的情况下提供致癌刺激。针对这种蛋白酶，tnf - α转换酶（TACE，也称为崩解素和金属蛋白酶17 [ADAM17]）与小分子抑制剂或sirna一起，通过阻止tgf - α两种关键生长因子的动员，逆转了乳腺癌细胞系的恶性表型。和amphiregulin。我们表明，tace依赖性配体脱落在一系列其他乳腺癌细胞系中普遍存在，并且在所有检查的情况下，都可抑制。利用现有的患者预后数据，我们证明了TACE和TGFA表达在人类乳腺癌中具有很强的相关性，可预测预后不良。由不当激活EGFR引起的肿瘤在多种组织中很常见，并且在大多数情况下，对当前的靶向治疗是难治的。本文提供的数据描述了在没有EGFR本身或下游途径成分突变的情况下，在肿瘤进展中实现组成性EGFR活性的分子机制，并表明这一重要的致癌途径可能有效地靶向受体的上游。
The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop that provides an oncogenic stimulus in the absence of proto-oncogene mutation. Targeting this protease, TNF-alpha-converting enzyme (TACE; also referred to as a disintegrin and metalloproteinase 17 [ADAM17]), with small molecular inhibitors or siRNAs reverted the malignant phenotype in a breast cancer cell line by preventing mobilization of 2 crucial growth factors, TGF-alpha. and amphiregulin. We show that TACE-dependent ligand shedding was prevalent in a series of additional breast cancer cell lines and, in all cases examined, was amenable to inhibition. Using existing patient outcome data, we demonstrated a strong correlation between TACE and TGFA expression in human breast cancers that was predictive of poor prognosis. Tumors resulting from inappropriate activation of the EGFR were common in multiple tissues and were, for the most part, refractory to current targeted therapies. The data presented here delineate the molecular mechanism by which constitutive EGFR activity may be achieved in tumor progression without mutation of the EGFR itself or downstream pathway components and suggest that this important oncogenic pathway might usefully be targeted upstream of the receptor.