Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway
Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway
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DOI：
10.1158/0008-5472.can-07-0599
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发表时间：
2007-08-01
期刊：
影响因子：
11.2
通讯作者：
Keyomarsi, Khandan
中科院分区：
文献类型：
--
作者：
Akli, Said;Van Pelt, Carolyn S.;Keyomarsi, Khandan
在肿瘤细胞中，周期蛋白E的失调导致五种低分子量（LMW）亚型的出现。当在乳腺癌细胞中过度表达时，这些形式的周期蛋白E诱导基因组不稳定，抵抗p21和p27的抑制，以及抵抗抗雌激素治疗。此外，周期蛋白E的LMW形式与乳腺癌患者的生存率降低密切相关。然而，LMW形式的周期蛋白E在乳腺癌肿瘤发生中的肿瘤学作用尚未确定。为此，我们在小鼠乳腺肿瘤病毒启动子的控制下，构建了表达cyclin E全长单链（M46A）、表达cyclin E全长和EL4亚型（EL1/EL4）或表达cyclin E （T1）的EL2/3亚型的转基因小鼠。与全长cyclin E相比，LMW cyclin E过表达可导致发育期乳腺生长延迟和哺乳期细胞形态异常。在LMW cyclin E转基因小鼠中，原发性乳腺肿瘤的形成和转移均明显增强。LMW cyclin E在小鼠乳腺上皮细胞中的过表达足以诱导124只小鼠中的34只（27%）发生乳腺腺癌，而67只小鼠中的7只（10.4%）只表达全长cyclin E （P < 0.05）。此外，25%的LMW细胞周期蛋白E荷瘤动物发生转移，而在全长细胞周期蛋白E背景下，只有8.3%的肿瘤发生转移（P < 0.05）。此外，LMW cyclin E过表达通过失去杂合性和ARE的自发和频繁失活来选择p53的失活。因此，LMW cyclin E过表达强烈地选择体内ARF-p53通路的自发失活，取消其保护检查点功能，加速恶性进展。
In tumor cells, cyclin E deregulation results in the appearance of five low molecular weight (LMW) isoforms. When overexpressed in breast cancer cells, these forms of cyclin E induce genomic instability, resistance to inhibition by p21 and p27, and resistance to antiestrogen therapy. Additionally, the LMW forms of cyclin E strongly correlate with decreased survival in patients with breast cancer. However, the oncologic role of the LMW forms of cyclin E in breast cancer tumorigenesis is yet to be determined. To this end, we generated transgenic mice expressing full-length cyclin E alone (M46A), full-length and the EL4 isoforms (EL1/EL4), or the EL2/3 isoforms of cyclin E (T1) under the control of the mouse mammary tumor virus promoter. Compared with full-length cyclin E, LMW cyclin E overexpression induces delayed mammary growth during the pubertal phase and abnormal cell morphology during lactation. Both primary mammary tumor formation and metastasis were markedly enhanced in LMW cyclin E transgenic mice. LMW cyclin E overexpression in mammary epithelial cells of mice is sufficient by itself to induce mammary adenocarcinomas in 34 of 124 (27%) animals compared with 7 of 67 (10.4%) mice expressing only the full-length cyclin E (P < 0.05). In addition, metastasis was seen in 25% of LMW cyclin E tumor-bearing animals compared with only 8.3% of tumors in the full-length cyclin E background (P < 0.05). Moreover, LMW cyclin E overexpression selects for inactivation of p53 by loss of heterozygosity and spontaneous and frequent inactivation of ARE Therefore, LMW cyclin E overexpression strongly selects for spontaneous inactivation of the ARF-p53 pathway in vivo, canceling its protective checkpoint function and accelerating progression to malignancy.