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Critical predictions as to the biological behavior, and thus the appropriate therapeutic strategy, of breast cancers can be made based upon the status of the estrogen receptor (ER). In support of DOD grant # DAMD-17-97-1-7069, our goal is to better understand the mechanisms by which ER controls the expression of target genes and therefore mediates the biological effects upon gene regulation and cell cycle progression. Our detailed studies of the regions of ER that control cell cycle progression in breast cancer cell lines have indicated an absolute requirement for the Activating Function-2 (AF-2) region of ER for hormone-dependent cell cycle progression. In many different classes of nuclear receptors, this area has been vigorously studied and has been shown to be important for the physical interaction between hormone bound receptors and coactivators. Our studies have demonstrated that mechanisms involving the chemical and structural modification of chromatin are critical for transcriptional responses to estrogen and may also be important for estrogen-dependent cell cycle progression.
Factors that mediate chemical or structural alterations of chromatin have been implicated as mediators of nuclear receptor function. Prominent in this diverse group of putative coactivators is the Steroid Receptor Coactivator-1 (SRC-1) and its related factors. These factors physically interact with liganded nuclear receptors and couple them to the multifunctional coactivators such as p3OO and CPB which have both intrinsic and associated histone acetyltransferase (HAT) activity. Other studies have suggested that factors involved in the structural remodeling of chromatin are required for nuclear receptor function. One such factor, the Brahma Related Gene-i (BRG- 1) potentiates nuclear receptor signaling and has been shown to be associated with liganded nuclear receptors. Like p3OO and CBP, we find that BRG-I exists in a stable complex with SRC- 1, and this complex can be recruited to a hormone bound estrogen receptor (ER). We demonstrate that in vitro the hormone-dependent association between BRG-1 and ER is mediated by SRC-1, and that structural determinants of ER required for SRC- I binding overlap with those required for the association between ER and BRG- 1. Furthermore, we present data that coactivation of ER signaling by either SRC- 1 or CBP requires BRG- 1. In addition we show that the BRG- 1-mediated coactivation of ER signaling is synergistically enhanced by inhibition of histone deactylation. These studies suggest that SRC- 1 functions as an adaptor that links two distinct classes of coactivators to nuclear receptor signaling.
In Breast Cancer: Cellular and Molecular Biology [Kluwer Academic Pub lishers, 1988], we tried to present an introduction to the emerging basic studies on steroid receptors, oncogenes, and growth factors in the regulation of normal and malignant mammary epithelium. The response to this volume was superb, indicating a tremendous interest in basic growth regulatory mechanisms governing breast cancer and controlling its malignant progres sion. In the two years since its publication, much new and exciting in formation has been published and the full interplay of regulatory mechanisms is now beginning to emerge. We have divided this book into four sections that we hope will unify important concepts and help to crystallize areas of consensus and/or disagreement among a diverse group of basic and clinical scientists working on the disease. The first section is devoted to studies on oncogenes, antioncogenes, proliferation, and tumor prognosis. The first chapter, by Sunderland and McGuire, introduces the characteristics of breast cancer as studied by patho logists to establish prognostic outcome. Of particular interest is a new proto oncogene called HER-2 (or neu), which is rapidly becoming accepted as a valuable new tumor marker of poor prognosis. The second chapter, by Lee Bookstein and Lee, introduces the best known antioncogene, the retinoblas toma antioncogene, whose expression is sometimes lost in breast cancer. Malignant progression appears to be influenced by the balance of proto oncogene and antioncogene expression.
Estrogens have been implicated to play a role in the development of breast cancer. The purpose of this book is to provide a comprehensive analysis of experimental, clinical and epidemiological evidence in support of the carcinogenicity of estrogens.
This book marks one of the achievements of the "Estrogen and Antiestrogen Action: Basic and Clinical Aspects" Wisconsin Clinical Cancer Center conference in June 1984. It is not intended to be a recount of the meeting proceedings but is, rather, a historical review of the development of this field of endeavor during the past 30 years. The chapters have been written by many of the leading experts in the field who were asked to recount the development of a particular area or laboratory idea in which they had been personally involved. The book is intended to provide both scientists and clinicians with a single-volume overview of both the basic principles of hormonal control of breast cancer and the recent clinical results from cooperative groups around the world.
Estrogens are associated with the development and progression of breast cancer in addition to their role in normal reproductive physiology, and estrogen receptors (ER) mediate the actions of estrogen in target tissues by regulating the expression of numerous biologically important target genes. The progression of human breast cancer and the development of resistance to endocrine therapies are thought to be associated with ER phosphorylation. We generated multiple combinations of ER phospho-mutants, at residues serine 104, 106, 118, 167, 236, and 305, and examined their impact on receptor half-life, the agonist and antagonist balance of selective estrogen receptor modulators (SERMs) and selective estrogen receptor downregulators (SERDs), the regulation of ER transcriptional activity, and stimulation of cell proliferation in response to estradiol and SERMs/SERD. We showed that changes in ER affecting the phosphorylation status of the receptor greatly impact receptor function and differential SERM and SERD modulated cellular responses that could contribute to resistance to endocrine therapies in breast cancer. We also studied the regulation of microRNAs (miRNAs) by estradiol and growth factors through ER and extracellular signal-regulated kinase 2 (ERK2) in order to understand their physiological impact on breast cancer. We identified nine miRNA- encoding genes harboring overlapping ER and ERK2 binding sites close to their transcription start sites, which require ER and ERK2 for transcriptional induction as well as estradiol- mediated miRNA regulation. We then identified TP63, a target of miR-101, miR-190 and miR- 196a2, and showed that TP63 plays an important role in estradiol- or growth factor-mediated cellular response in breast cancer cells (MCF-7 and MDA-MB-231) by increasing tumor cell growth and in vitro invasion mainly controlled by miR-196a2 action. These results suggest a tumor-suppressive role of miR-196a2 in regulating TP63 expression and the aggressive behavior of breast cancers.