Breast cancer is the most common cancer of women in the western world. Breast cancer patients do not die of their primary breast lesions, they die of metastatic disease, and this application will address the role of differentially expressed genes in the progression of breast cancer. Since none of the known genetic markers alone is a better prognostic indicator than tumor size and nodal status, we will collectively examine a number of genes that are related to tumor progression. In preliminary studies we have identified.several genes that are differentially expressed in highly metastatic rat mammary carcinoma cell lines. Some of the differentially expressed genes in highly.metastatic rat mammary cells have been partially sequenced and identified as cytokeritans, degradative enzymes, calcium-binding proteins, transcription factors- elongation factors, and mitogen-activated proteins. In some cases we have independent evidence for the involvement of certain gene products (annexins, cytokeritans, degradative enzymes) in the malignant properties of highly metastatic cells. The role of the other identified genes in conferring malignant characteristics and a functional conformation of the known genes in metastatic properties will be examined by transfection of full-length cDNAs or antisense constructs into recipient stable, benign or metastatic cells followed by assays for altered in vitro or in vivo properties, such as those involved in adhesion, invasion, growth, or metastasis. For example, we will measure adhesion to microvessel endothelial cells, invasion of extracellular matrix, response to paracrine motility and growth factors, and metastatic properties in F344 rats or nude (nu/nu) mice. Other cDNAs that we have isolated and sequenced are over- or under-expressed in metastatic mammary cells and are not homologous to any known gene. We will complete the sequencing of these genes and obtain full length cDNAs. Candidate full-length cDNAs will be transfected into recipient benign or highly metastatic cells, and we will test for changes in malignant cell properties. 'We will then examine if the expression of the candidate metastasis-associated gene products in clinical biopsies, including primary and secondary breast carcinomas, benign adenomas and other neoplastic and non-neoplastic lesions, predict the likelihood of recurrence of breast cancers at regional or distant sites. The goals of this project are to establish new genetic markers for metastasis and recurrence of breast cancer, identify genes whose differential expression is important in metastasis, and learn more about how multiple changes in gene expression confer the malignant and metastatic phenotype.
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