Ubiquitin Pathway Enzymes: Coactivators of Nuclear Hormone Receptor and Their Role in the Development of Breast Cancer

Abstract : Steroid hormones, estrogen and progesterone, and their intracellular receptors play an important role in the development and progression of breast cancer. Coactivator proteins modulate the biological activity of these hormone receptors. We have cloned an E3 ubiquitin-protein ligase enzyme, E6-associated protein (E6-AP) and E2 ubiquitin-conjugating enzyme, UbcH7 as coactivators of steroid hormone receptors. The purpose of this research is to explore the possibility that the altered expression of E6-AP and UbcH7 may contribute to the development of breast cancer. We have examined this possibility by studying the expression patterns of E6-AP, UbcH7 and estrogen receptor-alpha (ER) in various human breast cancer cell lines and breast tumor biopsy samples. Additionally, we have correlated the expression profile of E6-AP and UbcH7 with that of ER in breast tumor biopsies. Todate, we have examined 56 advanced stage human breast cancer biopsy samples for the expression profile of E6-AP, UbcH7 and ER. We found an inverse correlation between the expression of E6-AP and the expression of ER in these tumors. The Spearman Rank Correlation Coefficient is 0.38 and the p value is 0.004, indicating that this correlation is statistically significant. These data suggest a possible role of E6-AP in mammary gland development and tumorigenesis. However, we did not find any statistically significant eorrelation between the expression profile of UbcH7 and ER in these tumor samples. Presently, we are studying the expression profile of E6-AP, UbcH7 and ER in early and intermediate stage tumors. Another goal of this project is to create novel in vitro models in stable cell lines, which will overexpress coactivator proteins, E6-AP and UbcH7. In order to achieve this goal, we have already constructed the expression vectors for stable cell lines.