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Carcinogenesis Advance Access published online on December 13, 2006
Carcinogenesis, doi:10.1093/carcin/bgl239
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Liming Wang, Nandan Bhattacharyya2, Thangaiyan Rabi, Li Wang and Sipra Banerjee3

Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio 44195
2 Present address: Department of Biotechnology, Haldia Institute of Technology, West Bengal, India

3 To whom correspondence should be addressed. Tel: (216) 444-0631; Fax: (216) 445-6269; E-mail: banerjs{at}ccf.org

DNA polymerase ß (polß) is a major contributor to mammalian DNA damage repair through its gap-filling DNA synthesis and 5/-deoxyribose phosphate lyase activities. In this way, polß plays pivotal roles in the repair of oxidative DNA damage, replication, embryonic survival, neuronal development, meiosis, apoptosis and telomere function. A 36-kDa truncated polß{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 polß{Delta} and XRCC1 acts as dominant-negative mutant. In this study, the potential tumorigenic activity of polß{Delta} was examined in nude and transgenic mouse models. Mouse embryonic fibroblasts expressing polß{Delta} in the absence of endogenous polß exhibited increased susceptibility to N-methyl-N-nitrosourea (MNU)-induced morphological transformation as compared to cells expressing wild-type polß. This was accompanied by reduced gap-filling DNA synthesis activity. Anchorage-independent transformed cells derived from polß{Delta}-expressing MEFs induced 100% tumor occurrence in nude mice. To support these data, we established transgenic mice expressing polß{Delta} specifically in the mammary glands from a whey acidic protein (WAP) promoter-driven-transgene. This is the first report of transgenic mice with tissue-specific expression of polß{Delta}. MNU-induced tumor formation was analyzed in transgenic mice expressing polß{Delta} together with endogenous wild-type polß in their mammary glands and in normal control mice expressing only wild-type polß. 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 polß{Delta} display an enhanced sensitivity to MNU that likely underlies an increased susceptibility to tumorigenesis.

Key Words: DNA polß mutant • 19.4 mutant cells • transformed foci • tumorogenicity • transgenic mice

Authors 1 and 2 contributed equally to this study.


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