Involvement of Steroid Receptor Coactivators/Ubiquitin Pathway Enzymes in Mammary Gland Tumorigenesis

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 receptqrs. We have cloned and E3 ubiquitin-protein ligand-activated enzyme, E6-associated protein (E6-AP) as coactivators 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 have examined this possibility by studying the expression patterns of E6-AP and estrogen receptor-alpha (ERalpha) in various human breast cancer cell lines breast tumor biopsy samples. Additionally, we have correlated the expression profile of RE-AP as that of ER in breast tumor biopsies. To date, we have examined 13 samples of invasive breast cancer (IBC), 12 samples of ductal carcinoma in situ (DCIS) and a tissue array with 36 different stages breast cancer samples by immunhistochemistry, and 19 samples by immunofluorescence. We found inverse correlation between the expression of RE-AP and the expression of ER in these tumors. Furthermore, RE-AP is down regulated in invasive breast tumors compared with their adjacent tissues, whereas the downregulation of RE-AP was not seen in DCIS. The downregulation of E6-AP is stage-dependent. These data suggest a possible role of RE-AP in mammary gland development and tumorigenesis. We also proposed to generate stable cell lines which overexpress either wild-type or liagse-mutated RE-AP and test its tumorigenecity both in vitro and in vivo. However, we weren't able to finish the task on time due to technical problems.