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Mammary carcinogenesis in transgenic mice expressing a dominant-negative mutant of DNA polymerase beta in their mammary glands



Mammary carcinogenesis in transgenic mice expressing a dominant-negative mutant of DNA polymerase beta in their mammary glands



Carcinogenesis 28(6): 1356-1363



DNA polymerase beta (pol beta) is a major contributor to mammalian DNA damage repair through its gap-filling DNA synthesis and 5'-deoxyribose phosphate lyase activities. In this way, polo plays pivotal roles in the repair of oxidative DNA damage, replication, embryonic survival, neuronal development, meiosis, apoptosis and telomere function. A 36 kDa truncated polo beta Delta protein is expressed in human colorectal, breast, lung and renal carcinomas, but not in normal matched tissues. Interestingly, a binary protein-protein complex of pol beta Delta and X-ray cross-complementing group 1 acts as dominant-negative mutant. In this study, the potential tumorigenic activity of polo beta Delta was examined in nude and transgenic mouse models. Mouse embryonic fibroblasts (NmFs) expressing pol beta Delta in the absence of endogenous polo exhibited increased susceptibility to N-methyl-N-nitrosourea (MNU)-induced morphological transformation as compared with cells expressing wild-type (WT) polo. This was accompanied by reduced gap-filling DNA synthesis activity. Anchorage-independent transformed cells derived from pol beta Delta-expressing MEFs induced 100% tumor occurrence in nude mice. To support these data, we established transgenic mice expressing pol beta Delta specifically in the mammary glands from a whey acidic protein promoter-driven transgene. This is the first report of transgenic mice with tissue-specific expression of pol beta Delta. MNU-induced tumor formation was analyzed in transgenic mice expressing pol beta Delta together with endogenous WT pol beta in their mammary glands and in normal control mice expressing only WT pol beta. The latent period of tumor appearance was markedly shorter and tumor incidence was significantly higher in transgenic animals than in control animals treated under the same conditions. These results indicate that cells expressing the mutant pol beta Delta display an enhanced sensitivity to MNU that probably underlies an increased susceptibility to tumorigenesis.

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