Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway.
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.
Akli
Said
S
Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Van Pelt
Carolyn S
CS
Bui
Tuyen
T
Multani
Asha S
AS
Chang
Sandy
S
Johnson
David
D
Tucker
Susan
S
Keyomarsi
Khandan
K
D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019927:Cyclin E / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C417743:Cdkn2a protein, mouse; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53