Genetic instability favoring transversions associated with ErbB2-induced mammary tumorigenesis

Abstract

It has been argued that genetic instability is required to generate the myriad mutations that fuel tumor initiation and progression and, in fact, patients with heritable cancer susceptibility syndromes harbor defects in specific genes that normally maintain DNA integrity. However, the vast majority of human cancers arise sporadically, in the absence of deficiencies in known ''mutator'' genes. We used a cII-based mutation detection assay to show that the mean frequency of forward mutations in primary mammary adenocarcinomas arising in mouse mammary tumor virus-c-erbB2 transgenic mice harboring multiple copies of the bacteriophage genome was significantly higher than in aged-matched, wild-type mammary tissue. Analysis of the cII mutational spectrum within the mammary tumor genomic DNA demonstrated a >6-fold elevation in transversion mutation frequency, resulting in a highly unusual inversion of the transition͞transversion ratio characteristic of normal epithelium; frameshift mutation frequencies were unaltered. Arising oncogenic point mutations within the c-erbB2 transgene of such tumors were predominantly transversions as well. Data from this model system support the notion that elaboration of a mutator phenotype is a consequential event in breast cancer and suggest that a novel DNA replication͞repair gene is a relatively early mutational target in c-erbB2-induced mammary tumorigenesis.

Human ErbB-2 (Her-2) Transgenic Mice: A Model System for Testing Her-2 Based Vaccines

“…FVB NeuN mice crossed with C57BL/6 mice exhibit attenuated mammary tumor formation and increased tumor latency (32) and female mice develop tumors only after they experienced two to four pregnancies (33). The influence of strain background on mammary gland lesion incidence and phenotypes in WAP-TGF␣ Tgs has recently been described by Rose-Hellekant et al (34).…”

Modeling variation in tumors in vivo

“…The first study of this kind found no increase in the number of mutant lacI transgenes rescued from thymic tumors (43). However, two of three subsequent transgene rescue studies detected increased mutation (34,44,45). For example, a recent study reported that 5-fold more mutant lacZ transgenes were rescued from pristaneinduced mouse plasmacytomas than from normal splenocytes (45).…”

“…It was reasonable to anticipate that cells in the polyoma virus middle T antigen tumor model might exhibit reduced genetic stability, because Ras pathway activation has been linked to genetic instability (31)(32)(33). In addition, mouse mammary cancers induced by chronic c-erbB2 overexpression, which also disrupts cell cycle regulation, have been shown to be genetically unstable (34).…”

A new mutator phenotype in breast cancer?

“…In the 10-30% of human breast cancers with abnormal ErbB-2, it is found that overexpression by increase of transcription or amplification of the gene is involved, rather than activation by mutations. The mouse strain used by Liu et al in this study (4), therefore, uses the mouse mammary tumor virus long terminal repeat sequences to drive expression of the erbB-2 gene. This results in overexpression of the gene specifically in the mammary glands and has been shown to result in mammary tumors in mice (10,11).…”

“…The importance of the article by Liu et al (4) is the finding that a gene that is not thought to be involved in repair of DNA damage or maintenance of its integrity affects the occurrence of mutations. In particular, the type of mutations recovered in the mammary tumor tissues when ErbB-2 is overexpressed bears no resemblance to those found when mismatch repair is altered.…”