Genetic instability favoring transversions associated with ErbB2-induced mammary tumorigenesis.
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 lambda 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 transition/transversion 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 replication/repair gene is a relatively early mutational target in c-erbB2-induced mammary tumorigenesis.
Liu
Shiquan
S
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892-4264, USA.
Liu
Wenjing
W
Jakubczak
John L
JL
Erexson
Gregory L
GL
Tindall
Kenneth R
KR
Chan
Richard
R
Muller
William J
WJ
Adhya
Sankar
S
Garges
Susan
S
Merlino
Glenn
G
D000230:Adenocarcinoma / Q000235:genetics / Q000821:virology; D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D010582:Bacteriophage lambda / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts; D005787:Gene Frequency / Q000235:genetics; D007700:Kinetics; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
D018719:Erb-b2 Receptor Tyrosine Kinases