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From our current knowledge, it is obvious that estrogen action in volves more than reproduction and fertility. Rather, estrogens affect and influence a number of other organ systems such as the immune, cardiovascular and central nervous system as well as the gastrointes tinal tract, urinary tract and skeleton. The importance of estrogens and estrogen receptor activity is appreciated from the spectrum of significant physiological dysfunctions that occur when there is a loss The participants of the workshop VI Preface of the hormone or the receptor activity. Loss of estrogen, however (for instance during menopause), occurs with time and results in a variety of clinical conditions. We know that the developmental loss of estrogen, as seen in clinical cases of aromatase gene mutations and experimental models, has dramatic effects in both men and women alike. The evidence that these effects are mediated through the estrogen receptor(s) is based on similar but not always identical phenotypes as observed in experimental animal models of estrogen receptor mutations as well as the single clinical case of an estrogen receptor alpha mutant patient. Developing an understanding of the spectrum of estrogen in a variety of tissues related to the condition of estrogen loss is a major and highly active clinical as well as basic scientific research area. Following the discovery of a second estrogen receptor and possible receptor ligand-independent activity as well as the genomic and non genomic actions of estrogen, it is clear that the mechanisms of the effects of estrogen are multifaceted.
The discovery of ER by Dr. Elwood Jensen exactly 60 years ago has not only led to the birth of a whole new vital nuclear receptor research field but also made a rapid, direct and lasting impact on the treatment and prevention of breast cancer. Since that landmark discovery, tremendous progress has been made in our understanding of the molecular functions of ER and development of targeted therapies against ER pathways for breast cancer treatment. However, there is currently no book available addressing these discoveries and recent advancement in a historical and systematic fashion. This book is intended to provide comprehensive, most up-to-date information on the history and recent advancement of ER and breast cancer by world renowned leaders in the field. These chapters include the history of the discovery of ER; physiological and pathological roles of ER; recent discovery of ER cistrome, transcriptome and its regulation of noncoding RNAs such as microRNAs and enhancer RNAs in breast cancer; development and clinical practices of the first targeted therapy Tamoxifen and other antiestrogens for breast cancer treatment; structural basis of ER and antiestrogen actions; molecular insights into endocrine resistance; the role of ER mutants, ER-beta and environmental estrogens in breast cancer; and emerging state-of-the-art therapeutic approaches currently in development to overcome treatment resistance and future perspectives. The book will provide undergraduate and graduate students, basic scientists and clinical cancer researchers, residents, fellows, as well as clinicians, oncology educators and the general public a thorough and authoritative review of these exciting topics.
This volume presents the evolution of the authors' ideas about estrogen action and its modulation by a new group of drugs called SERMs (Selective Estrogen Receptor Modulators). The pioneering SERMs — tamoxifen and raloxifene — are known to have saved the lives of millions of women around the world and improved the health of millions more. Estrogen is the central hormone of women's health and reproduction. The book is a journey through 40 years of discovery and success in advancing women's health, with the prospect of improved innovation through medicinal chemistry for the future.
Estrogen receptors (ERs) are typical members of the superfamily of nuclear receptors that mainly function as ligand-inducible transcription factors that bind chromatin, as homodimers, at specific response elements. A tight reciprocal coupling between rapid 'non-genomic' and 'genomic' ER actions may also occur in many physiological processes. ERs have long been evaluated for their roles in controlling the expression of genes involved in vital cellular processes such as proliferation, apoptosis, and differentiation. Therefore, given the various and pleiotropic functions of ERs, the dysregulation of their pathways contributes to several diseases such as the hormone-dependent breast; endometrial and ovarian cancers; and neurodegenerative diseases, cardiovascular diseases, and osteoporosis. In this printed edition of the Special Issue, "Molecular Pathways of Estrogen Receptor Action," promising results on understanding the mechanisms underlying ER-mediated effects in various pathophysiological processes are represented, covering different roles of ER pathways in the tumorigenesis, the resistance to endocrine therapy, the dynamics of 3D genome organization, and cross-talk with other signaling pathways. This Special Issue also provides insight into the emerging roles of estrogen-signaling pathways in lung cancer, the tumor microenvironment, and the immune system.]
This is an Academic (Career Development) Award. Consistent with this award, the PI continues to ". appraise critically the state of the science in a particular aspect of breast cancer research and to forge new avenues of investigation." In this application, the studies are focused on antiestrogen resistance. With respect to the career development aspects, several original studies and reviews relevant to this application have been published, others have been submitted for publication. We continue to apply state-of-the- art technologies to addressing resistance, including the development of novel approaches to data mining and analysis. The studies of interferon regulatory factor-1 (IRF-1) continue. We have now completed the initial studies of the IRF-1 dominant negative IRF-1 construct. Immunohistologic methods for correlative studies on human breast tissues for nucleophosmin, NFxB, IRF-1 and X-box binding protein -1 (hXBP-1) have been completed on an initial study population. Several applications for funding arising directly from these studies have been submitted to NIH and DOD.