Am J Cancer Res 2012;2(2):168-177
Original Article
Tumor growth is suppressed in mice expressing a truncated XRCC1 protein
Christina Pettan-Brewer, John Morton, Sarah Cullen, Linda Enns, Keffy R M Kehrli, Julia Sidorova, Jorming Goh, Rebecca Coil,
Warren C Ladiges
Departments of Comparative Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA 98195, USA
Received January 3, 2012; accepted January 30; Epub February 2, 2012; Published February, 2012
Abstract: Tumor progression depends on the support of cells in the microenvironment, and is driven in part by the generation of
reactive oxygen species (ROS). ROS can damage DNA, and the repair of damaged DNA is a well-known process involved in
tumor initiation and promotion, but the role of DNA repair in tumor progression is not fully understood. In this regard the X-ray
cross complementing 1 (XRCC1) protein is known to orchestrate the assembly of repair complexes at sites of DNA single strand
breaks either directly or indirectly through repair of damaged bases, largely as the result of ROS-induced damage. XRCC1
polymorphisms have been shown to be associated with increased cancer. It was therefore of interest to investigate the effect of
XRCC1 gene mutations on cancer progression. In an attempt to make XRCC1 point mutant mice, we generated a truncated
protein (XRCC1tp) by the insertion of a neomycin cassette in intron12 of the XRCC1 gene. This unique finding allowed us to
investigate cellular and tumor progression phenotypes in mice associated with expression and function of an altered XRCC1
protein on one allele. XRCC1tp cells showed increased toxicity to MMS, enhanced MMS-induced depletion of NADH suggesting
increased PARP activity, and normal functional repair of MMS-induced DNA damage. Six months following treatment with the
alkylating carcinogen azoxymethane (AOM) at 10 mg/kg once a week for 6 weeks, XRCC1tp mice had a decrease in average
colon tumor volume of 14±3 mm3 compared to 34±4 mm3 in WT littermates (p≤ 0.03, N= 20/genotype). XRCC1tp mice had a 72
per cent decrease in B16 melanoma tumor burden compared to wt littermates. Average tumor volume in transgenic PyMT
metastatic breast cancer mice expressing XRCC1tp was 359 cubic mm in PyMT mice expressing XRCC1tp compared to 730
cubic mm in PyMT mice expressing XRCC1wt (p≤ 0.001, N= 20/genotype). These data suggest that the presence of an XRCC1
truncated protein alters XRCC1 function independent of DNA repair, and is associated with anti-tumor activity. (AJCR00000101).
Keywords: Tumor suppression, XRCC1, melanoma, colon cancer, breast cancer, PARP, apoptosis
Full Text PDF
Address all correspondence to:
Dr. Warren C Ladiges
Department of Comparative Medicine
School of Medicine
University of Washington
BOX 357190
Tel: (206) 685-3260
Fax: (206) 685-3006
Seattle, WA 98195
E-mail: wladiges@u.washington.edu
Original Article
Tumor growth is suppressed in mice expressing a truncated XRCC1 protein
Christina Pettan-Brewer, John Morton, Sarah Cullen, Linda Enns, Keffy R M Kehrli, Julia Sidorova, Jorming Goh, Rebecca Coil,
Warren C Ladiges
Departments of Comparative Medicine and Pathology, School of Medicine, University of Washington, Seattle, WA 98195, USA
Received January 3, 2012; accepted January 30; Epub February 2, 2012; Published February, 2012
Abstract: Tumor progression depends on the support of cells in the microenvironment, and is driven in part by the generation of
reactive oxygen species (ROS). ROS can damage DNA, and the repair of damaged DNA is a well-known process involved in
tumor initiation and promotion, but the role of DNA repair in tumor progression is not fully understood. In this regard the X-ray
cross complementing 1 (XRCC1) protein is known to orchestrate the assembly of repair complexes at sites of DNA single strand
breaks either directly or indirectly through repair of damaged bases, largely as the result of ROS-induced damage. XRCC1
polymorphisms have been shown to be associated with increased cancer. It was therefore of interest to investigate the effect of
XRCC1 gene mutations on cancer progression. In an attempt to make XRCC1 point mutant mice, we generated a truncated
protein (XRCC1tp) by the insertion of a neomycin cassette in intron12 of the XRCC1 gene. This unique finding allowed us to
investigate cellular and tumor progression phenotypes in mice associated with expression and function of an altered XRCC1
protein on one allele. XRCC1tp cells showed increased toxicity to MMS, enhanced MMS-induced depletion of NADH suggesting
increased PARP activity, and normal functional repair of MMS-induced DNA damage. Six months following treatment with the
alkylating carcinogen azoxymethane (AOM) at 10 mg/kg once a week for 6 weeks, XRCC1tp mice had a decrease in average
colon tumor volume of 14±3 mm3 compared to 34±4 mm3 in WT littermates (p≤ 0.03, N= 20/genotype). XRCC1tp mice had a 72
per cent decrease in B16 melanoma tumor burden compared to wt littermates. Average tumor volume in transgenic PyMT
metastatic breast cancer mice expressing XRCC1tp was 359 cubic mm in PyMT mice expressing XRCC1tp compared to 730
cubic mm in PyMT mice expressing XRCC1wt (p≤ 0.001, N= 20/genotype). These data suggest that the presence of an XRCC1
truncated protein alters XRCC1 function independent of DNA repair, and is associated with anti-tumor activity. (AJCR00000101).
Keywords: Tumor suppression, XRCC1, melanoma, colon cancer, breast cancer, PARP, apoptosis
Full Text PDF
Address all correspondence to:
Dr. Warren C Ladiges
Department of Comparative Medicine
School of Medicine
University of Washington
BOX 357190
Tel: (206) 685-3260
Fax: (206) 685-3006
Seattle, WA 98195
E-mail: wladiges@u.washington.edu
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American Journal of Cancer Research
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