Role of IGF-I in estrogen-receptor positive MCF7 breast cancer cells

Breast cancer arises when the genetic makeup of a normal breast epithelial cell is damaged in a manner that results in uncontrolled proliferation, enhanced survival, and metastasis. Because breast cancer cells are thought to develop from altered breast cells, they often continue to be sensitive to sex steroids such as estrogen and other extracellular signals such as growth factors and extracellular matrix proteins. The insulin-like growth factor (IGF) system has been shown to positively regulate all aspects of the malignant phenotype in breast cancer. The goal of this thesis was to gain a better understanding of how the IGF system interacts with estrogens and extracellular matrix proteins to influence malignant phenotypes in estrogen-receptor positive MCF7 breast cancer cells. The first objective was to identify the mechanism whereby IGF-I regulates estrogen receptoralpha-mediated gene expression in MCF7 breast cancer cells. I present evidence suggesting that IGF-I stimulation of the translational apparatus contributes to estrogen-stimulated gene expression and breast cancer growth. The second objective of this thesis was to determine whether ligation of integrins by the extracellular matrix protein fibronectin influenced IGF-I or estrogen biology in MCF7 breast cancer cells. The results indicate that occupancy of integrins by fibronectin is not required for estrogen-stimulated growth, or IGF-I-stimulated growth or survival. This is in contrast to the apparent requirement of integrin ligation by fibronectin for IGF-I-mediated migration in breast cancer cells. Delineation of how other receptor systems interact with the IGF system will allow for the development of more selective, comprehensive cancer therapies that would target all of the key molecules responsible for the malignant phenotype in a given tumor cell.