Microsatellite Instability In Cells Research Articles

Abstract 3899: Anti-cancer drugs increases microsatellite instability in human colorectal cancer cells

Abstract Manifested as microsatellite instability (MSI), DNA mismatch repair (MMR) deficiency is known to contribute to colorectal cancer pathogenesis and drug resistance. Growing evidence indicates that MMR deficiency is also widespread among secondary cancers in patients who have received chemotherapy. It is unclear what chemotherapeutic agents cause MMR deficiency. In this study, we aim at identifying the MSI-inducing anti-cancer drugs. To facilitate the identification, we developed an in-vivo dual fluorescent reporter system in a human colorectal cancer cell model using RFP that contains a microsatellite as the MSI reporter and GFP as the cell label. Based on flow cytometric analysis, we found that test anti-cancer drugs increased the MSI frequency in a dose-dependent manner. This was confirmed by fluorescent microscopy. With the NCI recommended markers, we detected a low frequency of MSI in cells after treated with a couple, but not all, of test anti-cancer drugs. Our cell-based MSI reporter assay will facilitate large scale screens of MSI-inducing and MSI-reducing drugs/compounds, which might provide treatment strategies for controlling therapy-related secondary cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3899. doi:10.1158/1538-7445.AM2011-3899

Is estradiol a genotoxic mutagenic carcinogen?

The natural hormone 17 beta-estradiol (E2) induces tumors in various organs of rats, mice, and hamsters. In humans, slightly elevated circulating estrogen levels caused either by increased endogenous hormone production or by therapeutic doses of estrogen medications increase breast or uterine cancer risk. Several epigenetic mechanisms of tumor induction by this hormone have been proposed based on its lack of mutagenic activity in bacterial and mammalian cell test systems. More recent evidence supports a dual role of estrogen in carcinogenesis as a hormone stimulating cell proliferation and as a procarcinogen inducing genetic damage. Tumors may be initiated by metabolic conversion of E2 to 4-hydroxyestradiol catalyzed by a specific 4-hydroxylase (CYP1B1) and by further activation of this catechol to reactive semiquinone/quinone intermediates. Several types of direct and indirect free radical-mediated DNA damage are induced by E2, 4-hydroxyestradiol, or its corresponding quinone in cell-free systems, in cells in culture, and/or in vivo. E2 also induces various chromosomal and genetic lesions including aneuploidy, chromosomal aberrations, gene amplification, and microsatellite instability in cells in culture and/or in vivo and gene mutations in several cell test systems. These data suggest that E2 is a weak carcinogen and weak mutagen capable of inducing genetic lesions with low frequency. Tumors may develop by hormone receptor-mediated proliferation of such damaged cells.

A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype.

Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ line mutations in MMR genes predispose kindreds to HNPCC suggest a "two-hit" inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells containing a wild-type hPMS2 allele. These results have significant implications for understanding the relationship between mutagenesis and carcinogenesis and the ability to generate mammalian cells with mutator phenotypes.