Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis

Darryl L. Hadsell, Kristen L. Murphy, Sharon G. Bonnette, Naomi Reece, Rodolfo Laucirica, Jeffrey M. Rosen

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Abstract

Mammary tumorigenesis was analysed in transgenic mice which overexpress des(1-3)hIGF-I (WAP-DES) and/or a mutant form of p53 (p53(172R-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 p53(172R-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 p53(172R-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 p53(172R-H).

Original languageEnglish (US)
Pages (from-to)889-898
Number of pages10
JournalOncogene
Volume19
Issue number7
DOIs
StatePublished - Feb 17 2000

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Carcinogenesis
Breast
Neoplasms
Breast Neoplasms
des-(1-3)-insulin-like growth factor 1
Genomic Instability
Aneuploidy
Human Mammary Glands
Transgenes
Insulin-Like Growth Factor I
Transgenic Mice
Adenocarcinoma
Genotype
Apoptosis
Incidence

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis. / Hadsell, Darryl L.; Murphy, Kristen L.; Bonnette, Sharon G.; Reece, Naomi; Laucirica, Rodolfo; Rosen, Jeffrey M.

In: Oncogene, Vol. 19, No. 7, 17.02.2000, p. 889-898.

Research output: Contribution to journalArticle

Hadsell, Darryl L. ; Murphy, Kristen L. ; Bonnette, Sharon G. ; Reece, Naomi ; Laucirica, Rodolfo ; Rosen, Jeffrey M. / Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis. In: Oncogene. 2000 ; Vol. 19, No. 7. pp. 889-898.
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