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

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 . Oncogene (2000) 19, 889 ± 898.

Transgenic mouse models of human breast cancer

“…With the exception of the MMTV/c-myc and MMTV/v-Ha-ras strains which died due to extensive lymphomas, inactivation of p53 resulted in a dramatic acceleration of mammary tumor progression. Mammary tumors found in these bi-transgenics also displayed increased aneuploidy as compared to those found in the mono-transgenic alone (Donehower et al, 1995;Hadsell et al, 2000). These results suggest that an absence of p53 predisposes mammary epithelial cells to genetic instability and tumor formation in the presence of some other initiating event such as a growth signal.…”

“…For example, mice de®cient in p53 have been crossed to a variety of transgenics including MMTV/ Wnt1 (Donehower et al, 1995), MMTV/c-myc (Elson and Leder, 1995), MMTV/v-Ha-ras (Hundley et al, 1997), WAP/IGF-1 (Hadsell et al, 2000) transgenic lines as well as BRCA1 heterozygotes (Cressman et al, 1999) and the conditional BRCA1 knockouts (Xu et al, 1999). With the exception of the MMTV/c-myc and MMTV/v-Ha-ras strains which died due to extensive lymphomas, inactivation of p53 resulted in a dramatic acceleration of mammary tumor progression.…”

Reversibility and recurrence of IGF-IR-induced mammary tumors

“…Overexpression of IGF-I (Hadsell et al, 2000) or IGF-II (Bates et al, 1995;Pravtcheva and Wise, 1998) in the mammary epithelium results in tumor development, albeit with long latency. Recently, mammary specific overexpression of a constitutively active IGF-IR (Carboni et al, 2005) or wildtype IGF-IR (Jones et al, 2007) has been shown to induce rapid tumor formation by 2 months of age.…”

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

“…Elevated levels of serum IGF-I and reduced levels of serum IGFBP-3 have been associated with an increased relative risk for breast cancer especially in premenopausal women under the age of 50 years (Hankinson et al, 1998). Finally, a direct association between IGF-I and IGF-II overexpression and mammary tumorigenesis has been established in transgenic mice (Bates et al, 1995;Pravtcheva and Wise, 1998;Hadsell et al, 2000).…”