Abstract
BackgroundAltered expression of DNA polymerase β (Pol β) has been documented in a large percentage of human tumors. However, tumor prevalence or predisposition resulting from Pol β over-expression has not yet been evaluated in a mouse model.Methodology/Principal FindingsWe have recently developed a novel transgenic mouse model that over-expresses Pol β. These mice present with an elevated incidence of spontaneous histologic lesions, including cataracts, hyperplasia of Brunner's gland and mucosal hyperplasia in the duodenum. In addition, osteogenic tumors in mice tails, such as osteoma and osteosarcoma were detected. This is the first report of elevated tumor incidence in a mouse model of Pol β over-expression. These findings prompted an evaluation of human gastrointestinal tumors with regard to Pol β expression. We observed elevated expression of Pol β in stomach adenomas and thyroid follicular carcinomas, but reduced Pol β expression in esophageal adenocarcinomas and squamous carcinomas.Conclusions/SignificanceThese data support the hypothesis that balanced and proficient base excision repair protein expression and base excision repair capacity is required for genome stability and protection from hyperplasia and tumor formation.
Highlights
Increasing evidence is emerging that a large percentage of human tumors have elevated expression of DNA polymerase b (Pol b) [1] and in many cases, mutations within the Pol b coding region results in over-expression of dysfunctional Pol b proteins [2]
Infection by several viruses associated with elevated cancer incidence, including chronic myelogenous leukemia (CML) [11], human papillomavirus 16 (HPV16) [12] and Epstein-Barr virus (EBV) [13], has been shown to induce the expression of Pol b to elevated levels
It is our hypothesis that altered expression of Pol b and the resulting imbalance in base excision repair (BER) can predispose to tumor formation
Summary
Increasing evidence is emerging that a large percentage of human tumors have elevated expression of DNA polymerase b (Pol b) [1] and in many cases, mutations within the Pol b coding region results in over-expression of dysfunctional Pol b proteins [2]. High levels of Pol b expression have been demonstrated in several human cancers and tumor cell lines [3,4,5,6]. Approximately 30% of human cancers express mutant or aberrant forms of Pol b proteins [2,14,15,16], leading to genomic instability and possibly conferring a mutator phenotype to cells [3,17,18]. Tumor prevalence or predisposition resulting from Pol b over-expression has not yet been evaluated in a mouse model
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