Grant: Operating Grant

Estrogens are physiologically important steroid hormones that regulate growth and differentiation in a broad range of target tissues including the mammary gland, uterus and ovary. The biological effects of estrogens are mediated through two forms of nuclear estrogen receptors (ER) named ERalpha and beta which control gene expression in conjunction with coregulatory proteins as ligand-regulated transcription factors. Inside cells, genes that are regulated by ER are assembled into a nucleoprotein structure known as chromatin that restricts the ability of these genes to be activated by ER and their coregulatory proteins. One of the roles of ER and their coregulatory proteins is to overcome the repressive effects of chromatin, allowing the genes to be appropriately activated. Although we understand the basic scheme of how estrogens control gene expression, we do not yet comprehend fully how ER and its coregulatory proteins work at chromatin level. The overall objective of this proposal is to achieve a better understanding of the role of chromatin architecture and its biochemical composition in transcriptional activation of ER-regulated genes. We will use molecular and cellular biology techniques in conjunction with biochemical tools that will help to unveil the functions of chromatin structure in gene expression. Together, these results should provide significant insight relevant to the understanding of the exploitation of ER and their coregulatory proteins as targets for drug therapy in human diseases, such as breast and ovarian cancers.