The investigation of cancer susceptibility in families or breeds of dogs is of critical importance to dog breeders and dog owners alike. Unlike other heritable conditions, genetic susceptibility to cancer may not manifest in disease until a dog has reached middle age, and long after it has achieved breeding potential. When present, this genetic susceptibility is most likely to be due to a process called loss of heterozygosity. Individuals inherit 2 copies of each gene upon conception; one from the sire, and one from the dam. Each of these gene copies is called an 'allele.' A family or a breed may have, through the course of time, lost a functional allele of a "tumor suppressor gene' through mutation. The affected individuals are heterozygous (that is, they have two different alleles, and only one is functional). These individuals will not develop disease (cancer), unless the second, functional copy of the "tumor suppressor gene' in question is mutated in a cell that retains the capacity to divide; for example, white blood cells that undergo division as they fight infections, pigment-producing cells that divide as a response to insult or injury to the skin, or bone cells that undergo division in the process of bone remodeling.

Tumor suppressor genes encode proteins that prevent or retard cell division. Tumor suppressor genes will even constrain or eliminate renegade cells that have initiated the path to cancer; thus mutations that disable these genes can be grouped in 3 broad categories. One group of tumor suppressor genes that includes p53and ATM among others, is responsible for controlling DNA repair. Cells can undergo spontaneous mutations, and these tumor suppressor genes must ensure that the mutant cells do not divide until the errors in their DNA sequence are repaired. Another group of tumor suppressor genes controls cellular aging or senescence. These genes encode proteins such as the cyclin-dependent kinase inhibitor p2l/Waf-1 and PTEN. In the examples above, tumor suppressor genes would be activated as it became necessary to terminate an immune response, at the end of the healing process of the skin, and when bone remodeling was complete.

Loss of the growth control pathways regulated by various tumor suppressor proteins such as those listed above, is associated with the origin and progression of lymphoma, leukemia, melanoma and osteosarcoma in humans and laboratory animals. Moreover, cancers that arise due to other mutations but that retain the expression of certain tumor suppressor genes such as pl6/Mts-1 and p2l/Waf-1 have been shown to respond more favorably to therapy, making these promising targets for genetic therapy of cancer.

Our laboratory has characterized some of the mechanisms that control tumor suppressor gene function in canine cells. For these projects, we have cloned the canine homologues of pl6/Mts-I and p2l/Waf-1. Additionally, in collaboration with the laboratory of Dr. D. Shippen we have cloned the genomic sequence for canine telomerase, another important gene that is important in cellular aging and cancer. We now plan to examine the frequency of mutations of these genes in canine lymphoma, melanoma, and osteosarcoma in families of Doberman Pinschers, Golden Retrievers, Boxers, and Rottweilers with high cancer prevalence. This will enable us to determine the relationship of tumor suppressor gene mutations with the prevalence of lymphoma, melanoma, and osteosarcoma in these high-risk breeds, as well as with prognosis and outcome. The results from our studies will provide tools that may predict the risk of a dog or its offspring to develop these devastating tumors. This information could have an immediate, visible, and long-lasting impact on canine health when used judiciously for breeding decisions. Additionally, it may be useful in the future to pave the way towards the development of advanced molecular therapies for canine cancer.

Dr. Modiano's work is supported by the following grant from the AKC Canine Health Foundation:

No. 1626: Significance of Tumor Suppressor Genes in Canine Cancer (Sponsored in part by the American Boxer Charitable Trust, Doberman Pinscher Foundation of America, Golden retriever Club of America in Honor of Carol Buckman, and the Medallion Rottweiler Club)

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