International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E16 Initiation and Progression of Polyoma Middle T-Induced Mammary Tumors is Controlled by Multiple Epistatically Interacting LocI

Le Voyer, T., Lu, Z., Lifsted, T., Williams, M. and Hunter, K. Fox Chase Cancer Center, Philadelphia, PA, USA

Previous studies from our laboratory demonstrated that the latency, tumor growth and metastatic progression of polyoma middle T-induced mammary tumor in an FVB/NJ inbred mouse background could be significantly altered by the introduction of different genetic backgrounds. In this study we extend these findings by mapping a number of interacting quantitative trait loci responsible the changes in phenotype.

Introduction of the I/LnJ inbred genetic background into the FVB/NJ-PyMT animal significantly accelerates the appearance of the primary tumor (35 vs. 57 days postnatal, p < 10-7). A backcross mapping panel was established and loci responsible for the tumor acceleration were detected on chrs. 15 and 9. Examination of the genotype/phenotype correlation revealed that the FVB/NJ but not the I/LnJ allele of the chr. 15 locus was associated with tumor acceleration, but was conditional on the presence I/LnJ allele on chr. 9. These loci, designated Apmt1 and Apmt2 map to syntenic regions associated with LOH in human breast cancer. These results suggest that in addition to loss of function, allelic variants of genes in these regions may contribute to age of onset in human breast cancer.

In addition to the acceleration of the tumor latency, introduction of the I/LnJ background into the FVB/NJ-PyMT mouse significantly suppresses the growth of the tumors. F1 animals between FVB/NJ-PyMT and I/LnJ accumulate only ~half the tumor tissue of the FVB/NJ-PyMT parent. Analysis of microvessel density of the tumors did not reveal a significant difference between the two genotypes. In addition, no significant differences in apoptosis has been detected in preliminary studies. A genome wide screen in the backcross revealed three loci significantly associated with tumor growth suppression. Two loci were present on proximal or central chr. 4 and one locus on proximal chr. 7. Examination of the genotype/phenotype correlation revealed like Apmt1 the FVB/NJ not the I/LnJ allele on chr. 7 was significantly associated with tumor suppression, and probably requires the FVB/NJ allele at one or both of the loci on chr. 4.


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