how multiple genes cooperate to cause cancer, focusing on breast cancer and leukemia
	Archibald Perkins, M.D., Ph.D. Associate Professor of Pathology Associate Professor of Molecular, Cellular and Developmental Biology Email: archibald.perkins@yale.edu Room: LH 409 Phone: (203) 785-6843 Lab: (203) 737-1245 Fax: (203) 785-7467 Web site

Cancer is a disease that results from a loss of the cell's ability to control vital decisions such as when to divide, when to differentiate, and when to die. It is a genetic disease since the underlying etiology is damage to key genes in the cell that help make these decisions. Our lab is interested in identifying genes involved in this process and uncovering their precise role, using the mouse as a model system.

We are currently studying two types of cancer: breast cancer and leukemia. In the mouse, both diseases can be induced by retroviral mutagenesis. Following infection, the proviral DNA from the retrovirus integrates into the cell? DNA and can alter the regulation of nearby genes. Malignant outgrowth of certain clones of infected cells can occur if the retrovirus alters the expression of genes involved in the regulation of growth or differentiation. It is possible to screen by hybridization for the retrovirus insertions in the DNA of the tumors that emerge. One can then molecularly clone the genes that have been tagged by the virus and are involved in oncogenesis.

This approach has led to the identification of a number of interesting oncogenes. One gene that is frequently activated in myelogenous leukemia is Evi-1. Evi-1 encodes a zinc finger protein that binds DNA in a sequence-specific manner, and acts as a regulator of transcription. We have identified several target genes for the protein, which is giving us insight into molecular events downstream to Evi-1 activation. We are also looking at how Evi-1 contributes to leukemia using transgenic mice. Another interest of our laboratory is to identify genes that cooperate with Evi-1 in the development of leukemia. This is being accomplished by using retroviruses to accelerate tumorigenesis in transgenic mice that overexpress Evi-1 and are susceptible to malignancy. With this approach, we hope to identify the other players in leuke-mogenesis and gain a molecular under-standing of the entire process.

Evi-1 likely plays an important role in mouse development, and to investigate this further, we are currently attempting to ?nock-out?the gene by homologous recombination, with the hope of gener-ating mice that lack Evi-1. Such a mutant would give us important insight into the role of Evi-1 in development.

Our lab is also using mice to study the interaction of various genes involved in breast cancer. This work centers on the role of Erbb2, a gene that is commonly amplified in human breast cancer, and p53, a gene that is commonly mutated in human breast cancer. Erbb2 can cause mammary tumors when overexpressed in transgenic mice, and encodes a cell surface receptor that initiates mitogenic signals when stimulated by certain extracellular factors, one of which is heregulin. By over-expressing both Erbb2 and heregulin in transgenic mice, we hope to see how these two entities interact in tumorigenesis. In addition, we are examining how a mutated p53 and overexpressed Erbb2 cooperate in mammary tumors in mice. We are also trying to find other genes that cooperate in this process using the retrovirus MMTV, which, like the leukemogenic retroviruses, can molecularly tag genes that act together with Erbb2 to cause mammary tumors. Thus we are using the mouse as a system to look at interactions between different genes involved in cancer, and also to identify new genes that cause cancer. These two complementary pursuits will hopefully yield a better understanding of this complex disease.

Selected Publications

Perkins, A.S., R. Fishel, N.A. Jenkins, and N.G. Copeland (1991) Evi-1, a murine zinc finger proto-oncogene, encodes a sequence-specific DNA-binding protein. Mol. Cell. Biol. 11:2665-2674.

Perkins, A.S., J.A. Mercer, N.A. Jenkins, and N.G. Copeland (1991). Patterns of Evi-1 expression in embryonic and adult tissues suggests that Evi-1 plays an important regulatory role in mouse development. Development 111:479-487.

Brannan, C., Perkins, A.S. , Ratner, N., Nordlund, M., Reid, S.W., Buchberg, A., Jenkins, N.A., Parada, L.F., Copeland, N.G. (1994). Inactivation of the neurofibromatosis type 1 gene leads to abnormalities of neural crest derived tissues. Genes and Dev. 8:1019-1029.

Perkins, A.S., and J.H. Kim (1996). Zinc fingers of EVI1 fail to bind to the GATA motif by itself but require the core site GACAAGATA for binding. J. Biol. Chem. 271:1104-1110.

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