Carcinogenesis Advance Access published online on July 2, 2009
Carcinogenesis, doi:10.1093/carcin/bgp159
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Genetic Mapping of Mom5, a novel modifier of ApcMin-induced intestinal tumorigenesis
1 Department of Applied Chemistry and Microbiology (Nutrition), P.O. Box 66, FIN-00014 University of Helsinki, Finland
2 Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
3 Department of BioSciences and Nutrition, Karolinska Institute, NOVUM, S-14186 Huddinge, Sweden
4 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204
Address correspondence to: Karen A. Gould, Department of Genetics, Cell Biology and Anatomy, 985805 Nebraska Medical Center, Omaha, NE, Phone: (402) 559-2456, Fax: (402) 559-7328, E-mail: kagould{at}unmc.edu
Marja Mutanen, Department of Applied Chemistry and Microbiology, Division of Nutrition, P.O. Box 66, FIN-00014 University of Helsinki, Finland, Phone: +358-9-191 58270, FAX: +358-9-191 58269, E-mail: Marja.Mutanen{at}Helsinki.fi
The initial purpose of this study was to assess the role of ERβ in intestinal tumorigenesis by examining the effects of an estrogen receptor β knockout (ERβ–/–) on ApcMin mice. In order to accomplish this goal on a uniform genetic background, we were required to backcross the ERβ knockout from the 129P2 genetic background to the B6 genetic background for 10 generations. Mid way through this process, we performed a test cross in which mice from the N5 backcross generation of the ERβ knockout strain were intercrossed with ApcMin/+ mice to obtain ApcMin/+ ERβ+/+, ApcMin/+ ERβ+/– and ApcMin/+ ERβ–/– mice. Intestinal tumorigenesis in the N5F2 mice was evaluated at 14 weeks of age. The analysis of the impact of ERβ in the N5 cross was complicated by segregating 129P2-derived alleles that affected tumor number and were unlinked to ERβ. Genetic linkage analysis of this cross permitted the localization of a single genetic modifier of tumor number in ApcMin/+ mice. This locus, Modifier of Min 5 (Mom5), maps to proximal mouse chromosome 5; the 129P2 allele of this locus is associated with a 50% reduction in mean intestinal tumor number. Through in silico analysis and confirmatory sequencing, we have identified the Rint-1 gene as a strong candidate for Mom5.
Key Words: colon cancer • Apc • QTL • modifier • Rint-1
* These authors contributed equally
Received November 6, 2008; revised June 15, 2009; accepted June 20, 2009.