Transcriptional Functions of Nuclear Receptors in Cancer Cells
Breast cancer will constitute greater than 30% of all new cancers diagnosed in women this year. Steroid hormones, such as estrogen and progesterone, play an important role in the development and treatment of breast cancer. These receptors represent critical sensors of environmental exposures on reproduction and development while being subject to epigenetic regulation of their activity. Despite intensive efforts, the mortality resulting from this disease has not decreased significantly over the last decade. Of the treatments currently available, hormone therapy remains one of the most effective means of clinical intervention. In my laboratory, the scientists have undertaken detailed analysis of the mechanism of action of the steroid receptors and clinically important steroid receptor antagonists which are used to block their action. Our experiments are focused on the role of chromatin and epigenetics that are critical to understanding their function. It is hoped that these basic research studies will provide new insight into the role that steroid hormone receptors play in breast cancer and the possible development of novel and effective treatments.
As major determents of homeostasis and development, the steroid receptors are particularly important targets for environmental endocrine disruptors that have many human health consequences. While these agents are extremely diverse in structure, activity and bioavailability, many if not all activities are mediated via these receptors. Consequently a molecular description of the mechanism of action of these receptors will provide a precise underpinning to evaluate their physiological and clinical impact with a specific relevance to breast cancer. Our efforts are informed by the overwhelming evidence that a full understanding of transcriptional control requires an appreciation for roles played by the chromatin structure of target genes and the molecular machines that are required to unleash the regulatory potential of steroid receptors. To achieve this we have focused our attention on the mammalian BRG1 chromatin remodeling complex and the 26S proteasome, their interactions with and regulation by the glucocorticoid and progesterone receptors. The activity of these complexes has been evaluated in the context of the chromatin within human and mouse cells with particular attention to the RNA polymerase phosphorylation and the acetylation/methylation of the core histones.
More recently my group has embarked on an exciting new area of research that examines the fundamental nature of human embryonic stem cells by characterizing the chromatin remodeling and chromatin modifying complexes that are present in these cells. This is complimented by analyses of the master regulatory proteins Oct4, Sox2 and Nanog to determine the genetic and epigenetic targets that underlie the biological program for stem cells. The nature of many of our models, human and mouse breast cancer cells as well as embryonic stem cells, is indicative of our active interest in women's health and breast cancer specifically. Our research plan discovers and evaluates the contributions that chromatin remodeling proteins, 26S proteasome, nuclear receptors, pluripotency factors, mirRNAs and promoter chromatin architecture make to regulate the transcriptional response to endogenous and environmental signals in normal, embryonic and cancerous cells.
Dr. Archer received a Ph.D. in Biochemistry in 1987 at Queen's University, Kingston, Ontario, Canada, after which he did postdoctoral training on chromatin gene transcription and steroid receptors at the National Cancer Institute, in Bethesda. In 1992, Dr. Archer joined the University of Western Ontario in Canada, as a National Cancer Institute of Canada Scientist. Dr. Archer joined the NIEHS in 1999 as Head, Chromatin Structure and Gene Expression. Dr. Archer was appointed as Chief, Laboratory of Molecular Carcinogenesis in February 2003. Dr. Archer has made numerous original and important contributions to the study of chromatin structure/function, epigenetics and gene transcriptional regulation in breast cancer cells while publishing ~100 peer reviewed manuscripts.