Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2021-07-22 , DOI: 10.1038/s41418-021-00836-6 Sylvain Lefort 1 , Amal El-Naggar 2, 3 , Susanna Tan 1, 4 , Shane Colborne 5 , Gian Luca Negri 2 , Davide Pellacani 1 , Martin Hirst 5, 6, 7 , Barry Gusterson 8 , Gregg B Morin 5, 9 , Poul H Sorensen 2, 10 , Connie J Eaves 1, 9
Breast cancer heterogeneity has made it challenging to identify mechanisms critical to the initial stages of their genesis in vivo. Here, we sought to interrogate the role of YB-1 in newly arising human breast cancers as well as in established cell lines. In a first series of experiments, we found that short-hairpin RNA-mediated knockdown of YB-1 in MDA-MB-231 cells blocked both their local tumour-forming and lung-colonising activity in immunodeficient mice. Conversely, upregulated expression of YB-1 enhanced the poor in vivo tumorigenicity of T47D cells. We then found that YB-1 knockdown also inhibits the initial generation in mice of invasive ductal carcinomas and ductal carcinomas in situ from freshly isolated human mammary cells transduced, respectively, with KRASG12D or myristoylated-AKT1. Interestingly, increased expression of HIF1α and G3BP1, two YB-1 translational targets and elements of a stress-adaptive programme, mirrored the levels of YB-1 in both transformed primary and established MDA-MB-231 breast cancer cells.
中文翻译:
人乳腺细胞转化的从头和细胞系模型揭示了 Yb-1 在人乳腺癌多个阶段中的重要作用
乳腺癌的异质性使得在体内确定对其起源的初始阶段至关重要的机制变得具有挑战性。在这里,我们试图探究 YB-1 在新出现的人类乳腺癌以及已建立的细胞系中的作用。在第一系列实验中,我们发现短发夹 RNA 介导的 MDA-MB-231 细胞中 YB-1 的敲低阻断了它们在免疫缺陷小鼠中的局部肿瘤形成和肺定植活性。相反,YB-1的上调表达增强了T47D细胞体内较差的致瘤性。然后,我们发现 YB-1 敲低还抑制了小鼠最初用KRAS G12D转导的新鲜分离的人乳腺细胞的侵袭性导管癌和导管原位癌的产生或肉豆蔻酰化-AKT1。有趣的是,HIF1α 和 G3BP1(两个 YB-1 翻译靶点和应激适应程序的元素)的表达增加反映了转化的原发性和已建立的 MDA-MB-231 乳腺癌细胞中 YB-1 的水平。