ETIOLOGY AND PROGRESSION OF BREAST CANCER

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One out of every eight women in the United States will be affected by breast cancer in her lifetime. Breast cancer is a multi-faceted disease that is influenced by many factors including genetics, as well as endo- genous and exogenous environmental factors. We are interested in determining the environmental agents that influence the course of this disease and how these environmental factors interplay with products of breast cancer susceptibility genes. We are specifically investigating the function of the breast and ovarian susceptibility gene, BRCA1. We have found that decreased expression of BRCA1 using antisense cDNA results in an increase in tumorigenicity and anchorage-independence, as well as a growth advantage in normal growth restrictive conditions, such as low estrogen in ovarian cancer cells. In addition, loss of BRCA1 may result in resistance to apoptotic stimuli induced by hydrogen peroxide. Additional investigation of the expression of BRCA1 protein revealed the distinct expression of an alternately spliced form of the BRCA1 protein. We are currently trying to develop an inducible expression system for BRCA1 that will allow BRCA1-mediated signal transduction to be elucidated. We have succeeded in expressing exogenous BRCA1 in cells using a genomic expression vector. The advantage of this system is that the typical toxicity that is observed with BRCA1 overexpression does not occur. In addition, BRCA1 expression may be modulated similar to the endogenous gene. Finally, the role of the IGFI and the progression of breast carcinoma is being investigated. We have shown that decreased expression of IGFI by dietary restriction can reduce the formation of advanced bladder carcinomas in mice. We have now extended this observation to breast tumor development and have shown that decreased activation of the IGF pathway by treatment of cells with the soluble IGFIR results in a significant decrease of invasion potential and metastases of the breast cell line, MDAMB435.