Abstract
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.
Highlights
Cyclin E is a G1 cyclin necessary for the transition from G1 to S phase of the normal cell cycle [1]
To assess the oncogenic role of cyclin E-low molecular weight (LMW) as compared with full-length cyclin E, we examined the consequences of overexpressing these isoforms in the mammary glands of transgenic mice using the mammary tumor virus (MMTV) promoter
When we combined and compared the incidence of metastasis in all tumors formed in M46A animals, independent of p53 background, to incidence of metastasis in all tumors formed in EL1/EL4 and T1, again independent of p53 background, we found a statistically significant increase in the metastatic potential of the tumors formed in LMW cyclin E transgenic animals (Fig. 5C; P < 0.001)
Summary
Cyclin E is a G1 cyclin necessary for the transition from G1 to S phase of the normal cell cycle [1]. Deregulation of cyclin E accelerates the entry of the cells into S phase but causes inefficient progression through S phase. The untimely expression of cyclin E has been shown to interfere with the replication complex assembly. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-07-0599 as cells exit mitosis [2]. Constitutive overexpression of cyclin E protein at all phases of the cell cycle is one of the features observed in breast cancer cell cycle and thought to result in premature DNA replication, genomic instability [4, 5], and carcinogenesis [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
