Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis.
Mammary tumorigenesis was analysed in transgenic mice which overexpress des(1-3)hIGF-I (WAP-DES) and/or a mutant form of p53 (p53172R-H). Nonlactating, multiparous WAP-DES mice exhibited hyperplastic lesions termed mammary interepithelial neoplasia (MIN) which constitutively expressed WAP-DES. By 23 months of age, 53% of the WAP-DES mice developed mammary adenocarcinomas. A 75% reduction in both apoptosis and proliferation was observed in the normal mammary glands of WAP-DES mice. Mammary tumor incidence in WAP-DES/p53 bitransgenic mice was similar to that of WAP-DES and 2 - 3-fold greater than that of nontransgenic and p53172R-H females. Tumor latency, however, was reduced by 8 months in bitransgenic mice as compared to mice of the other three genotypes. Aneuploidy was frequently observed in tumors from bitransgenic and p53172R-H mice, but not from mice expressing only the WAP-DES transgene. Expression of IGFBP3 was elevated in tumors from WAP-DES, but not bitransgenic mice, indicating an alteration in the p53/IGF-I axis. These studies indicate that overexpression of des(1-3)hIGF-I increases the frequency of MIN and stochastic mammary tumors and that the appearance of tumors displaying genomic instability is accelerated by mutant p53172R-H. Oncogene (2000) 19, 889 - 898.
Hadsell
D L
DL
Department of Pediatrics, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Murphy
K L
KL
Bonnette
S G
SG
Reece
N
N
Laucirica
R
R
Rosen
J M
JM
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; C058957:insulin-like growth factor 1, des-(1-3)-; D007334:Insulin-Like Growth Factor I