Khan Iman A, Yoo Byong H, Rak Janusz, Rosen Kirill V
Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Canada.
Department of Pediatrics, Dalhousie University, Halifax, Canada.
Oncotarget. 2017 Oct 31;8(62):105383-105396. doi: 10.18632/oncotarget.22194. eCollection 2017 Dec 1.
Detachment of non-malignant epithelial cells from the extracellullar matrix (ECM) triggers their growth arrest and apoptosis. Conversely, carcinoma cells can grow without adhesion to the ECM. This capacity for anchorage-independent growth is thought to be critical for tumor progression. ErbB2/Her2 oncoprotein is overproduced by a significant fraction of breast cancers and promotes anchorage-independent tumor cell growth by poorly understood mechanisms. In an effort to understand them we found that in order to produce ErbB2, detached breast cancer cells require the activity of an ErbB2 effector protein kinase Mek and that Mek-driven ErbB2 expression is neccesary for anchorage-independent growth of such cells. We observed that Mek inhibition does not alter ErbB2 mRNA levels in detached cancer cells and that ErbB2 protein loss induced by this inhibition can be blocked by a lysosomal inhibitor. We also noticed that an increase of the density of cancer cells detached from the ECM downregulates a Mek effector protein kinase Erk and causes ErbB2 loss. Those cells that survive after ErbB2 loss display resistance to trastuzumab, an anti-ErbB2 antibody used for ErbB2-positive breast cancer treatment. Thus, Mek-induced ErbB2 stabilization in detached breast cancer cells is critical for their ability to grow anchorage-independently and their trastuzumab sensitivity.
非恶性上皮细胞与细胞外基质（ECM）脱离会引发其生长停滞和凋亡。相反，癌细胞可不依赖与ECM的黏附而生长。这种不依赖贴壁生长的能力被认为对肿瘤进展至关重要。相当一部分乳腺癌会过度产生ErbB2/Her2癌蛋白，其通过尚不清楚的机制促进不依赖贴壁的肿瘤细胞生长。为了弄清楚这些机制，我们发现，脱离的乳腺癌细胞要产生ErbB2需要一种ErbB2效应蛋白激酶Mek的活性，并且Mek驱动的ErbB2表达对于此类细胞的不依赖贴壁生长是必需的。我们观察到，抑制Mek不会改变脱离的癌细胞中ErbB2的mRNA水平，并且这种抑制诱导的ErbB2蛋白丢失可被溶酶体抑制剂阻断。我们还注意到，从ECM脱离的癌细胞密度增加会下调一种Mek效应蛋白激酶Erk并导致ErbB2丢失。在ErbB2丢失后存活的那些细胞对曲妥珠单抗具有抗性，曲妥珠单抗是一种用于治疗ErbB2阳性乳腺癌的抗ErbB2抗体。因此，Mek诱导的脱离的乳腺癌细胞中ErbB2的稳定对于其不依赖贴壁生长的能力及其对曲妥珠单抗的敏感性至关重要。
