Ribozyme Targeting of Steroid Receptor Co-Activators: A Therapeutic Approach to Breast Cancer

摘要

The gene of the nuclear receptor coactivator AIB1 is amplified in breast cancer cell lines as well as in breast tumor tissue. AIBl mRNA is often highly expressed in primary breast tumors and has been shown that AIBl enhances estrogen and progesterone dependent transcription in vitro. Therefore, it has been postulated that AIBl contributes to the development of breast cancer. However, it is currently not known what the precise role of AIBl is in the development of breast cancer. To address this question, we established MCF-7 breast cancer cell lines in which we can regulate AIBl levels with ribozymes in order to determine the impact of reduced AIBl gene expression on the phenotype and angiogenic or invasive properties of breast cancer cells. Here we report that depletion of endogenous ATBl levels reduced steroid hormone signaling via the estrogen receptor-alpha or progesterone receptor-beta as well as estrogen- mediated inhibition of apoptosis and cell growth. Furthermore, we demonstrate that upon reduction of endogenous AlBl expression, estrogen-dependent colony formation in soft agar and tumor growth of MCF-7 cells in nude mice was decreased. We have now also demonstrated that reduction in AIBl levels significantly decreases the invasive and motile behavior of MCF-7 cells, in particular in the focal adhesion factor of the MCF-7 cells. We conclude that AIB1 exerts a rate-limiting role for hormone dependent human breast tumor growth.