Acceleration of mouse mammary tumor virus-induced murine mammary tumorigenesis by a p53 172H transgene: influence of FVB background on tumor latency and identification of novel sites of proviral insertion.
We previously showed that a mammary-specific dominant-negative p53 transgene (WAP-p53(172H)) could accelerate ErbB2-induced mammary tumorigenesis in mice, but was not tumorigenic on its own. To identify other genes that cooperate with WAP-p53(172H) in tumorigenesis, we performed mouse mammary tumor virus (MMTV) proviral mutagenesis. We derived F1, N2, and N4/N5 mice from p53(172H) transgenic FVB mice backcrossed onto MMTV+ C3H/He mice. Results show the latency of MMTV tumorigenesis is correlated with FVB contribution. F1 tumors had the shortest latency (217 days), had a higher rate of metastasis, and were less differentiated than the N2 and N4/N5 tumors. The latency was 269 days in N2 mice, and lengthened to 346 days in N4/N5 mice. p53(172H) significantly accelerated MMTV tumorigenesis only in N2 mice, indicating cooperativity between p53(172H) and MMTV in this cohort. To identify genes that may be causally involved in MMTV-induced mammary tumorigenesis, we identified 60 sites of proviral insertion in the N2 tumors. Among the insertions in p53(172H) transgenic tumors were 10 genes not previously found as sites of MMTV insertion including genes involved in signaling (Pdgfra, Pde1b, Cnk1), cell adhesion (Cd44), angiogenesis (Galgt1), and transcriptional regulation (Olig1, Olig2, and Uncx4.1). These may represent cellular functions that are likely not deregulated by mutation in p53.
Chatterjee
Gouri
G
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023. USA.
Rosner
Andrea
A
Han
Yi
Y
Zelazny
Edward T
ET
Li
Baolin
B
Cardiff
Robert D
RD
Perkins
Archibald S
AS
D000818:Animals; D002471:Cell Transformation, Neoplastic; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D008321:Mammary Glands, Animal / Q000473:pathology / Q000821:virology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016296:Mutagenesis; D015996:Survival Rate; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D016662:Virus Integration
D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53