RGD Reference Report - 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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Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway.
Authors:	Akli, S Van Pelt, CS Bui, T Multani, AS Chang, S Johnson, D Tucker, S Keyomarsi, K
Citation:	Akli S, etal., Cancer Res. 2007 Aug 1;67(15):7212-22.
RGD ID:	2289229
Pubmed:	PMID:17671189 (View Abstract at PubMed)
DOI:	DOI:10.1158/0008-5472.CAN-07-0599 (Journal Full-text)
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 ARF. 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.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
CCNE1	Human	Neoplasm Metastasis	disease_progression	ISO	Ccne1 (Mus musculus)	protein:altered processing	RGD
Ccne1	Rat	Neoplasm Metastasis	disease_progression	ISO	Ccne1 (Mus musculus)	protein:altered processing	RGD
Ccne1	Mouse	Neoplasm Metastasis	disease_progression	IDA		protein:altered processing	RGD

Objects Annotated

Genes (Rattus norvegicus)

Ccne1 (cyclin E1)

Genes (Mus musculus)

Ccne1 (cyclin E1)

Genes (Homo sapiens)

CCNE1 (cyclin E1)

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Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway.