1. Cancer Res. 2003 Sep 15;63(18):5808-12.
Congenic rats reveal three independent Copenhagen alleles within the Mcs1
quantitative trait locus that confer resistance to mammary cancer.
Haag JD(1), Shepel LA, Kolman BD, Monson DM, Benton ME, Watts KT, Waller JL,
Lopez-Guajardo CC, Samuelson DJ, Gould MN.
(1)McArdle Laboratory for Cancer Research, University of Wisconsin, Madison,
Wisconsin 53706, USA.
It has previously been shown that the Copenhagen (COP) rat contains several
genetic loci that contribute to its mammary tumor-resistant phenotype after
7,12-dimethylbenz(a)anthracene (DMBA) administration. One of these loci, mammary
carcinoma susceptibility 1 (Mcs1), is located on the centromeric end of
chromosome 2 and appears to act in a semidominant fashion. To confirm the
existence and independent action of this locus and also aid in the identification
of the physical location of the Mcs1 gene, congenic lines were generated by
transferring the Mcs1 COP allele onto a Wistar Furth (WF) genetic background.
Male carriers were genotyped using microsatellite markers spanning 20-30 cM of
the Mcs1 locus. One of the congenic lines minimally retained the COP allele at
D2Mit29 on the centromeric end of chromosome 2 and extended distally to D2Rat201.
Heterozygous Mcs1 carrier rats were interbred, and the female offspring were
treated with DMBA. The female rats from the Mcs1 congenic line that carried one
or two COP alleles of the Mcs1 region had a significantly reduced (65 and 85%,
respectively) tumor development (P < 0.001) compared with rats carrying zero COP
alleles at this locus. A WF.COP-D2Mit29/D2Rat201 homozygous congenic strain
derived at the N10 generation was treated with DMBA, and the COP homozygous rats
developed 1.5 +/- 0.3 carcinomas/rat versus 6.3 +/- 0.5 in WF control rats (P <
0.0001). Fine mapping of this congenic interval using several recombinant lines
identified three genetic loci within the Mcs1 congenic region that independently
supported a tumor resistance phenotype. These genetic loci have been termed
Mcs1a, Mcs1b, and Mcs1c. In rats for which each locus was homozygous for the COP
allele, tumor development was reduced by approximately 60% compared with
littermate controls. The identification of these independent loci within the Mcs1
COP allele provide a model of the genetic complexity of cancer.
PMID: 14522903 [PubMed - indexed for MEDLINE]
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