Suppression of Neu-induced mammary tumor growth in cyclin D1 deficient mice is compensated for by cyclin E
Suppression of Neu-induced mammary tumor growth in cyclin D1 deficient mice is compensated for by cyclin E
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DOI：
10.1038/sj.onc.1205025
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发表时间：
2002-01-10
期刊：
影响因子：
8
通讯作者：
Maroulakou, IG
中科院分区：
文献类型：
--
作者：
Bowe, DB;Kenney, NJ;Maroulakou, IG
受体酪氨酸激酶 HER2/Neu 和细胞周期调节基因细胞周期蛋白 D1 的扩增和/或过度表达通常与人类乳腺癌相关。我们通过在细胞周期蛋白 D1 缺乏的背景下培养过度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 的缺失会抑制由野生型或激活的 Neu 突变体诱导的乳腺肿瘤形成，从而分别促进肿瘤发生的多步和单步进展。这些数据表明，细胞周期蛋白 D1 是乳腺肿瘤发生中 Neu 介导的信号转导途径优先需要的。值得注意的是，由于细胞周期蛋白 E 的补偿，35% 的突变型 Neu/cyclin D1(-/-) 小鼠恢复了乳腺肿瘤潜能。因此，细胞周期蛋白 D1 和 E 的共同靶点对于调节乳腺肿瘤发生中的 Neu 功能非常重要。我们的结果表明，细胞周期蛋白 D1 和 E 的组合抑制可能有助于治疗 Neu 诱发的恶性肿瘤。
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.