McCoy Erica L, Iwanaga Ritsuko, Jedlicka Paul, Abbey Nee-Shamo, Chodosh Lewis A, Heichman Karen A, Welm Alana L, Ford Heide L
Program in Molecular Biology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
J Clin Invest. 2009 Sep;119(9):2663-77. doi: 10.1172/JCI37691. Epub 2009 Aug 24.
Six1 is a developmentally regulated homeoprotein with limited expression in most normal adult tissues and frequent misexpression in a variety of malignancies. Here we demonstrate, using a bitransgenic mouse model, that misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner. The neoplastic lesions induced by Six1 had an in situ origin, showed diverse differentiation, and exhibited progression to aggressive malignant neoplasms, as is often observed in human carcinoma of the breast. Strikingly, the vast majority of Six1-induced tumors underwent an epithelial-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt signaling, including cyclin D1. Interestingly, Six1 and cyclin D1 coexpression was found to frequently occur in human breast cancers and was strongly predictive of poor prognosis. We further show that Six1 promoted a stem/progenitor cell phenotype in the mouse mammary gland and in Six1-driven mammary tumors. Our data thus provide genetic evidence for a potent oncogenic role for Six1 in mammary epithelial neoplasia, including promotion of EMT and stem cell-like features.
Six1是一种在发育过程中受到调控的同源异型蛋白，在大多数正常成年组织中表达有限，而在多种恶性肿瘤中经常出现表达异常。在此，我们使用双转基因小鼠模型证明，人Six1在成年小鼠乳腺上皮中的异常表达以剂量依赖的方式诱导多种组织学亚型的肿瘤。Six1诱导的肿瘤性病变起源于原位，表现出不同的分化，并发展为侵袭性恶性肿瘤，这在人类乳腺癌中经常观察到。引人注目的是，绝大多数Six1诱导的肿瘤经历了上皮-间质转化（EMT），并表达了激活的Wnt信号的多个靶点，包括细胞周期蛋白D1。有趣的是，Six1和细胞周期蛋白D1的共表达在人类乳腺癌中经常出现，并且强烈预示着预后不良。我们进一步表明，Six1在小鼠乳腺和Six1驱动的乳腺肿瘤中促进了干细胞/祖细胞表型。因此，我们的数据为Six1在乳腺上皮肿瘤形成中的强大致癌作用提供了遗传学证据，包括促进EMT和干细胞样特征。
