A transgenic mouse model for mammary carcinogenesis

Abstract

Missense mutations in the p53 tumor suppressor occur frequently in human breast cancer and in¯uence both the prognosis and response to chemotherapy. Amino acid 175 (equivalent to murine 172) is the second most common site of missense mutations in p53 in human breast cancer. Over 95% of these mutations are arginine-to-histidine (R-H) substitutions resulting in a gain-of-function, and not merely a dominant-negative phenotype. Transgenic mice expressing a p53 172 R ± H construct targeted to the mammary gland by means of a whey acidic protein (WAP) promoter were characterized as a model system in order to determine the speci®c e ects of this mutation on mammary tumorigenesis. Although transgene expression alone had no apparent e ect on normal mammary development, transgenic mice treated with the chemical carcinogen dimethylbenz(a)anthracene developed tumors with much shorter latency than did control littermates and had a greater tumor burden. Tumors arising in transgenic mice did not exhibit either decreased apoptosis or increased cell proliferation relative to tumors arising in nontransgenic littermates, but did display increased genomic instability. Large pleiomorphic nuclei were visible in many tumors from transgenic mice, and DNĀ ow analysis con®rmed the presence of signi®cant aneuploid cell populations. Since these transgenic mice develop very few spontaneous tumors, while accelerating carcinogen-and oncogene-mediated tumorigenesis, this mouse model will, therefore, be useful in the investigation of early events in mammary tumorigenesis. It may also be used as a preclinical model to test newly developed chemotherapeutic strategies.

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

“…The p53 172R-H mice develop few spontaneous mammary tumors. However, susceptibility to mammary tumorigenesis is markedly increased in p53 172R-H mice following treatment with the carcinogen DMBA (Li et al, 1998) or with coexpression of oncogenes such as neu (Li et al, 1997). This supports the suggestion that this gain-of-function mutant is capable of cooperating with a number of di erent factors known to in¯uence mammary tumorigenesis.…”

“…Previous studies (Li et al, 1998;Wang et al, 1998) have demonstrated aneuploidy in both mammary and skin tumors occurring in DMBA-treated mice carrying a targeted p53 172R-H transgene. To determine if p53 172R-H expression results in a predisposition to aneuploidy in the context of the WAP-DES transgene, FACS analysis was conducted on tumor cell nuclei.…”

“…To determine if this interaction is capable of increasing the mammary tumor incidence in mice, a previously characterized (Li et al, 1998) line of transgenic mice which overexpresses a mutant form of p53 containing an arginine to histidine substitution at codon 172 (p53 172R-H ) was crossed with the WAP-DES mice.…”

“…Mammary tissue sections were stained for apoptosis or BrdU incorporation using previously described procedures (Li et al, 1997(Li et al, , 1998. Labeling index was obtained by counting labeled and unlabeled epithelial cells in 8 ± 12 (about 1000 cells total) ®elds at 10006 magni®cation.…”

“…Inactivation of p53 has been described as one of the mechanisms by which T-antigen causes tumors (Symonds et al, 1994). Recently, transgenic mice which exhibit mammary gland-speci®c expression of a murine p53 possessing an arginine to histidine substitution at codon 172 (p53 172R-H ) have been characterized (Li et al, 1998). The murine 172 R-H mutation is analogous to a missense mutation (p53 175 R-H ) that is frequently observed in human breast cancer (Hainaut et al, 1997) and has been associated with a poor prognosis (Aas et al, 1996).…”