Role of Nuclear Hormone Receptor Co-activator, E6-associated Protein (E6-AP) in the Development of Breast Cancer

摘要

Steroid hormones, estrogen and progesterone, and their intracellular receptors play an important role in the development and progression of breast cancer. Coactivators modulate the biological activity of these hormone receptors. We have cloned an E3 ubiquitin-protein ligase enzyme, E6-associated protein (E6-AP) as a coactivator of steroid hormone receptors. The purpose of this research is to explore the possibility that the altered expression of E6-AP may contribute to the development of breast cancer. We propose to explore this by developing animal models for overexpression and loss of function of E6-AP and then relate these observations to the clinical setting by studying the expression patterns of E6-AP in various human breast tumors. In this report, we report that we have successfully generated E6-AP overexpression models and an E6-AP null mouse line. Our data from these models suggest that overexpression of E6-AP in mammary gland results in impaired mammary gland development. Furthermore, loss of E6-AP expression results in an overly developed mammary gland compared to that of control mammary gland. These mice exhibit increased ductal branching and alveolar buds. However, the overexpression of transgene E6- AP and loss of function of E6-AP have no significant effects on the pregnant mammary glands. Additionally, we also show that E6-AP modulates the p53 expression in these animals. E6-AP possesses two independent and separable functions: coactivation and ubiquitin-protein ligase activity. Our data suggest that increased ductal branching and alveolar branching in E6-AP null mice are results of loss of ligase activity of F6-AP. To study the expression profile of E6-AP in human breast tumors, we examined 100 different human breast cancer biopsy samples. We found an inverse correlation between the expression of E6-AP and the expression of estrogen receptor-alpha in these tumors.