Bowe Damon B, Kenney Nicholas J, Adereth Yair, Maroulakou Ioanna G
Laboratory of Cancer Genomics, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, SC 29425, USA.
Oncogene. 2002 Jan 10;21(2):291-8. doi: 10.1038/sj.onc.1205025.
Amplification and/or overexpression of the receptor tyrosine kinase HER2/Neu and the cell cycle regulatory gene cyclin D1 are frequently associated with human breast cancer. We studied the functional significance of cyclin D1 in Neu-induced mammary oncogenesis by developing mice overexpressing either wild-type or mutant Neu in a cyclin D1 deficient background. The absence of cyclin D1 suppresses mammary tumor formation induced by the wild-type or activated mutant form of Neu, which promote multi- and single-step progression of tumorigenesis, respectively. These data indicate that cyclin D1 is preferentially required for Neu-mediated signal transduction pathways in mammary oncogenesis. Significantly, 35% of mutant Neu/cyclin D1(-/-) mice regained mammary tumor potential due to compensation by cyclin E. Thus, shared targets of cyclins D1 and E are important in modulating Neu function in mammary tumorigenesis. Our results imply that the combinatorial inhibition of cyclins D1 and E might be useful in the treatment of malignancies induced by Neu.
受体酪氨酸激酶HER2/Neu的扩增和/或过表达以及细胞周期调控基因细胞周期蛋白D1，常与人类乳腺癌相关。我们通过培育在细胞周期蛋白D1缺陷背景下过表达野生型或突变型Neu的小鼠，研究了细胞周期蛋白D1在Neu诱导的乳腺肿瘤发生中的功能意义。细胞周期蛋白D1的缺失抑制了由野生型或活化突变型Neu诱导的乳腺肿瘤形成，这两种类型的Neu分别促进肿瘤发生的多步骤和单步骤进展。这些数据表明，在乳腺肿瘤发生过程中，细胞周期蛋白D1是Neu介导的信号转导通路所优先需要的。值得注意的是，35%的突变型Neu/细胞周期蛋白D1(-/-)小鼠由于细胞周期蛋白E的补偿作用而恢复了乳腺肿瘤发生的潜能。因此，细胞周期蛋白D1和E的共同靶点在调节乳腺肿瘤发生中Neu的功能方面很重要。我们的结果表明，联合抑制细胞周期蛋白D1和E可能对治疗由Neu诱导的恶性肿瘤有用。
