Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY.
Int J Cancer. 2013 Dec 1;133(11):2587-95. doi: 10.1002/ijc.28295. Epub 2013 Jun 21.
The epidermal growth factor receptor (EGFR) is frequently expressed in triple-negative breast cancer (TNBC) and is a marker of poor prognosis in this patient population. Because activating mutations in this kinase are very rare events in breast cancer, we screened breast tumor gene expression profiles to examine the distribution of EGFR ligand expression. Of the six known EGFR ligands, transforming growth factor alpha (TGFα) was expressed more highly in triple-negative breast tumors than in tumors of other subtypes. TGFα is synthesized as a transmembrane precursor requiring tumor necrosis factor alpha converting enzyme (TACE)/ADAM17-dependent proteolytic release to activate its receptor. In our study, we show that an inhibitor of this proteolytic release blocks invasion, migration and colony formation by several TNBC cell lines. Each of the effects of the drug was reversed upon expression of a soluble TGFα mutant that does not require TACE activity, implicating this growth factor as a key metalloproteinase substrate for these phenotypes. Together, these data demonstrate that TACE-dependent TGFα shedding is a key process driving EGFR activation and subsequent proliferation and invasion in TNBC cell lines.
表皮生长因子受体（EGFR）在三阴性乳腺癌（TNBC）中经常表达，并且是该患者人群预后不良的标志物。由于在乳腺癌中这种激酶的激活突变是非常罕见的事件，我们筛选了乳腺癌肿瘤基因表达谱，以检查 EGFR 配体表达的分布。在六种已知的 EGFR 配体中，转化生长因子α（TGFα）在三阴性乳腺癌肿瘤中的表达高于其他亚型的肿瘤。TGFα 作为跨膜前体合成，需要肿瘤坏死因子α转化酶（TACE）/ADAM17 依赖性蛋白水解释放来激活其受体。在我们的研究中，我们表明，这种蛋白水解释放的抑制剂可阻断几种 TNBC 细胞系的侵袭、迁移和集落形成。该药物的每种作用在表达不需要 TACE 活性的可溶性 TGFα 突变体时均被逆转，表明这种生长因子是这些表型的关键金属蛋白酶底物。总之，这些数据表明，TACE 依赖性 TGFα 脱落是驱动 EGFR 激活以及随后的 TNBC 细胞系增殖和侵袭的关键过程。
