Dynamics of Estrogen Receptor Transcription Complex Assembly in Breast Cancer

摘要

Estrogen plays a critical role in the development and progression of breast cancer. The biological activities of estrogen are mediated by estrogen receptors (ER). In addition, a large number of proteins termed cofactors are involved in ER signaling. Therapeutic agents, such as tamoxifen, also bind ER, but block proliferation in breast cells. However, tamoxifen increases the risk of endometrial cancer. We have used chromatin immunoprecipitation (ChIP) to investigate cofactor involvement in ER signaling in vivo and to understand the mechanisms underlying the different actions of tamoxifen in breast and endometrial cells. We have found that differences in cofactor expression underlie tissue-specific effects of tamoxifen. Chip, in combination with tiled arrays of individual chromosomes, has been used to identify distant ER-binding sequences that regulate gene expression. Gene expression profiling has been used to identify differential regulation of ER targets in breast and endometrial cells, and these targets have been evaluated for their ability to regulate cell proliferation. The detailed understanding of tissue and ligand-dependent changes in gene expression gained through these studies will lead to more effective therapies for ER-dependent breast cancer.