International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

Identification and Mapping of Mammary Tumor Metastasis Efficiency Genes

Lukes, L1., LeVoyer, T., Lifsted, T., Williams, M. and Hunter, K1
Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111 and
Laboratory of Population Genetics, DCEG/NCI/NIH, 41 Library Drive, 41/D702, Bethesda, MD 20892.

Metastatic progression is a major cause of mortality in cancer patients. Dissemination of the primary tumor throughout the body often precludes surgical removal, and the metastases are often refractory to chemotherapy. Comprehensive understanding of metastatic progression would be of enormous benefit for the prevention and treatment of disseminated tumors. However, due to the complexity of the process, involving many regulatory events (both positive and negative), the factors critical to the in vivo process of metastasis are not completely understood.

To gain a better understanding of the genetic components involved in tumor dissemination, we have initiated a genetic screen for metastasis efficiency modifier genes, using the FVB/N-TgN(MMTVPyMT) transgenic mouse. The PyMT mouse was bred to 33 different inbred lines, and the effect of introducing a new genetic background on metastatic disease assessed. Two inbred strains were identified that significantly suppressed the number of metastatic lesions observed in the lungs (> 10 x reduction). To date we have performed four independent QTL mapping experiments to obtain initial genetic map location of the gene or genes responsible for the suppression of metastatic lesions. At least three different chromosomal regions have been tentatively identified that significantly (p < 0.001) suppress the numbers of pulmonary metastatic lesions. We are currently confirming the assignment of these loci prior to initiating high resolution genetic mapping and positional and candidate gene cloning strategies to identify and characterize these metastasis efficiency genes.


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