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The somatotropic axis is one of the major hormonal systems regulating growth, development, and metabolism. Growth hormone (GH) can act directly on target tissues or indirectly by stimulating insulin-like growth factor (IGF-I) through the JAK2-Stat5 pathway. The first objective of this dissertation was to test whether exogenous GH could stimulate growth, development, and insulin resistance in the absence of functional Stat5 proteins. Wild type (WT) and Stat5 mutant (Stat5DN) mice were treated with exogenous GH for 4 weeks. Stat5DN mice grew at a slower rate and had lower hepatic IGF-I expression and plasma IGF-I than WT animals. GH stimulated growth in WT animals but had absolutely no effect in Stat5DN mice. GH increased hepatic IGF-I expression and plasma IGF-I in WT mice but failed to do so in Stat5DN mice. GH-stimulated IGF-I expression also occurred in the muscle and adipose of WT mice only. GH-treated Stat5DN mice were protected from GH-induced insulin resistance. This protection was associated with lack of GH-stimulated expression of p85a mRNA in insulin sensitive tissues. GH plays a critical role in mammary development through its modulation of mammary production of IGF-I and IGF binding proteins (IGFBPs). One component of the IGF system that has not been studied in mammary development is the acid labile subunit (ALS). ALS is thought to function exclusively by forming ternary complexes with IGF-I and IGFBP-3 or -5 to build a reservoir of circulating IGF-I. The second objective was to evaluate the role of ALS in mammary gland development using null ALS mice. Null ALS mice had three specific mammary defects, namely delayed ductal elongation, impaired ductal branching in early pregnancy, and delayed involution following lactation. In contrast, mammary development during late ALS mRNA was pregnancy and lactation appeared normal in null ALS mice. detected in the mouse mammary gland, and levels of expression were comparable to liver during pregnancy, lactation, and involution. Therefore, mammary defects seen in null ALS mice cannot be attributed solely to disruption of the circulating IGF system and could relate partly to local ALS expression.
Insulin-like growth factor (IGF)-I is a widely expressed growth factor with diverse effects on many tissues throughout development and in adult life. The purpose of this work is to provide detailed and updated information on the role of the growth hormone (GH)-IGF axis in fetal and postnatal development, as well as its physiological functions and implications in pathology.
Proceedings of the European Cooperation in the Field of Scientific and Technical Research (COST 825) Symposium on Mammary Gland Biology, held September 16-18, 1999, in Tours, France. It is difficult to overstate the evolutionary and functional significance of mammary tissue in biology. Substantial progress has been made by researchers in various disciplines, particularly over the last fifteen years, towards realizing the potential of this tissue to yield powerful experimental models for morphogenesis and tissue development; for cellular differentiation; for the biosynthesis and secretion of proteins, lipids, small molecules and inorganic salts; and for the coordination and regulation of these processes. More recently, the possibility of exploiting the secretory epithelial cells of mammary tissue as `cell factories' has become a reality and the recombinant production by lactating animals of an increasing number of proteins, valuable both in the pharmaceutical and `nutraceutical' fields, is in progress or under development. Also in this sphere of agricultural production, genetic as well as nutritional technologies are under investigation and exploitation to optimize milk composition for various end-uses - for instance in food process and manufacture. The possibilities of deriving health benefit from the bioactive properties of some of the minor constituents of milk are emerging to counter the highly-publicized negative health impact of excessive consumption of saturated animal fats. In human nutrition and medicine, the mammary gland is both a source of nutrition to the neonate and a potential health threat to the adult female - breast cancer remains the major single cause of female mortality in most developed countries. This volume provides a unique glimpse into our understanding, at the cutting edge of a variety of disciplines, of this versatile and extraordinary tissue, at the birth of the twenty-first century.
Over the past five years there has been an explosion of "targeted therapies" for cancer treatment. In most cases, these therapies have been based on pre-clinical data showing that specific molecules play an important role in regulating the malignant phenotype. In breast cancer, there is compelling rationale that such targeted strategies should be successful. Targeting of estrogen receptor ? (ER?) has proven to be a successful way to reduce breast cancer risk, decrease the risk of death and recurrence in an adjuvant setting, and remains the first choice of treatment for advanced disease. With this success, it is hoped that other molecular pathways could also be successfully exploited. This publication reviews the role of the insulin-like growth factors (IGFs) in breast cancer. Over 100 years ago George Beatson made an intuitive leap connecting breast cancer therapy with ovarian function He removed the ovaries from a premenopausal woman with breast cancer; he reasoned that ovarian function regulated normal mammary gland function, therefore the ovaries may influence the malignant phenotype. Other discussion included cover the function of IGF action in the normal mammary gland using mouse model systems where expression and function can be manipulated and the patterns of expression of the IGFs, their binding proteins, and their receptors in the normal gland.
For more than seventy years evidence has accumulated documenting the existence of a bi-directional communication network between growth hormone and the immune system. In the past twenty years there has been a tremendous proliferation of information detailing the workings of the growth hormone and insulin-like growth factor axis. A multitude of growth factors and binding proteins have been identified. More and more evidence supporting the important role of the growth hormone IGF network in the well functioning of the normal immune system has been documented. Clearly the challenge today is not to prove, but to understand, the neuroimmune regulatory role of GLH in its entire complexity. The ultimate goal of this volume and of all the other volumes of this series is to promote the understanding of the science and to ease human suffering.
Insulin-like growth factors are ubiquitously expressed and are crucial for growth and function of almost all cells. Together with their binding proteins and receptors, they form a widely studied biological system involving many proteins and characterized by complex interactions. In addition to its significance in growth and development, the insulin-like growth factor system also has important roles in a wide variety of pathological states. This has led to interest in the therapeutic potential of insulin-like growth factors and their binding proteins as candidate drug targets. This comprehensive book contains current information on both basic science and clinical aspects of IGFs and their regulatory proteins, with emphasis on their relevance to cancer.