Gastrointestinal Hyperplasia with Altered Expression of DNA Polymerase β

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.

DNA polymerases and cancer

“…In non-small-cell lung cancer 156 , higher POLH expression correlated with poorer outcome 156 . Increased expression of POLB has been reported in gastric 152,157 , uterine 152 , prostate 152 , ovarian 152 and thyroid 158 carcinomas, and forced overexpression of POLB in cells can interfere with normal replication, causing mutagenesis 159, 160 . Transgenic mice overexpressing Polb have a number of pathologies, including increased development of osteosarcoma 158 .…”

Base excision repair and cancer

“…Overexpression in Chinese hamster ovary cells has been shown to induce cellular transformation and genomic instability [294,295]. Using a transgenic mouse model, Sobol and colleagues demonstrated that overexpression of Pol β in certain organs, such as the stomach, resulted in hyperplasia [296]. Overexpression of Pol β can lead to imbalances in BER, which has been shown in Saccharomyces cerevisiae to result in a mutator phenotype [297].…”

Targeting DNA Polymerase ß for Therapeutic Intervention

“…High levels of Polβ expression have been demonstrated in several human cancers and tumor cell lines [140]. We, and others, have observed elevated expression of Polβ in gastrointestinal tumors and cancers from the esophagus, colon and pancreas [9, 141–143]. In addition, chronic myelogenous leukemia (CML) [144] and infection by human papillomavirus 16 (HPV16) [145] or Epstein-Barr virus (EBV) [146] leads to elevated expression of Polβ.…”

“…Polβ has been implicated in several cellular functions, including genome stability [3], telomere maintenance [4–6] and meiosis [7]. Defects in Polβ have been linked with cancer [8, 9], aging [10], neurodegeneration [11, 12] and its expression is critical for the cellular response to environmental and chemotherapeutic genotoxins [13]. This latter function involves its primary role as the major DNA polymerase in the base excision repair (BER) pathway.…”