Journal Article

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

Liming Wang, Nandan Bhattacharyya, Thangaiyan Rabi, Li Wang and Sipra Banerjee

in Carcinogenesis

Volume 28, issue 6, pages 1356-1363
Published in print June 2007 | ISSN: 0143-3334
Published online December 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl239
Mammary carcinogenesis in transgenic mice expressing a dominant-negative mutant of DNA polymerase β in their mammary glands

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DNA polymerase β (polβ) is a major contributor to mammalian DNA damage repair through its gap-filling DNA synthesis and 5′-deoxyribose phosphate lyase activities. In this way, polβ plays pivotal roles in the repair of oxidative DNA damage, replication, embryonic survival, neuronal development, meiosis, apoptosis and telomere function. A 36 kDa truncated polβΔ protein is expressed in human colorectal, breast, lung and renal carcinomas, but not in normal matched tissues. Interestingly, a binary protein–protein complex of polβΔ and X-ray cross-complementing group 1 acts as dominant-negative mutant. In this study, the potential tumorigenic activity of polβΔ was examined in nude and transgenic mouse models. Mouse embryonic fibroblasts (MEFs) expressing polβΔ in the absence of endogenous polβ exhibited increased susceptibility to N-methyl-N-nitrosourea (MNU)-induced morphological transformation as compared with cells expressing wild-type (WT) polβ. This was accompanied by reduced gap-filling DNA synthesis activity. Anchorage-independent transformed cells derived from polβΔ-expressing MEFs induced 100% tumor occurrence in nude mice. To support these data, we established transgenic mice expressing polβΔ 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 polβΔ. MNU-induced tumor formation was analyzed in transgenic mice expressing polβΔ together with endogenous WT polβ in their mammary glands and in normal control mice expressing only WT polβ. 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 polβΔ display an enhanced sensitivity to MNU that probably underlies an increased susceptibility to tumorigenesis.

Journal Article.  6736 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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