Breast Tumor Kinetics in Mice Overexpressing Cyclin E and Heterozygous for Tumor Suppressor p53 or Rb
Abstract
Deregulated expression of cyclin E may play a role in tumorigenesis through the induction of genomic instability. We generated mice heterozygous for the tumor suppressor p53 or Rb and with an inducible transgene of either wildtype human cyclin E or a hyperstable allele (T380A) expressed in the mammary epithelia. While no mammary tumors were observed in any Rb heterozygote strain, there was synergy between the hyperstable T380A transgene and p53 heterozygosity; increasing mammary tumor penetrance from 8% and 12% respectively in p53 and T380A controls to 50% in the doubly engineered mice (p<0.0001). However, despite the increase in tumor penetrance there was no decrease in latency with the onset of mammary tumorigenesis approximately corresponding to reproductive senescence. Tumor cells demonstrated loss of p53 heterozygosity and constitutive expression of the cyclin E transgene. These preliminary data strongly support the hypothesis that deregulated expression of cyclin E induces tumorigenesis through genomic instability and suggests that inactivation of p53 and deregulated expression of cyclin E may confer a growth advantage in mammary epithelial cells. However, in this mouse model, not unlike human sporadic cases, these tumors may not form until the onset of reproductive senescence when hormonal influence may play a key role.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADA407356
Entities
People
- Adrian P. Smith
- John A. Lee
- Steven I. Reed
Organizations
- Scripps Research