The Effects of Novel Serms on Endothelial and Epithelial Tumor Cell Estrogen Receptor Activation

by Kaimakliotis, Palvos Zacharias

Abstract (Summary)
Premenopausal women are relatively protected against the development of coronary heart disease, when compared with age-matched men. This difference dissolves after menopause and is accepted to be hormonally mediated. Despite recent clinical controversies in the use of hormone replacement therapy in postmenopausal women, there have been numerous in vitro and in vivo studies that demonstrate favorable effects of estrogen on the endothelium. The Bender laboratory has shown that 17[beta]-estradiol (E[subscript]2) rapidly induces nitric oxide (NO) release from human endothelial cells (EC) in vitro. This occurs through a c-Src/phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, in a rapid fashion in the absence of modulated gene expression. In addressing how these membrane growth factor receptor-type responses to a steroid hormone could occur, the Bender laboratory also demonstrated that EC have more than one form for ER[alpha]. The classical ER[alpha], a 66kDa protein, is predominantly cytosolic and nuclear, and comprises a minority of the ERs in most EC. ER46, a 46kDa protein, is a product of an alternative transcript splice form, and represents a majority of the ERs in most EC. ER46 has a predilection for membrane targeting, and more efficiently transduces the favorable EC activation responses to E[subscript]2 described above. Given the controversy surrounding the effects of hormone replacement therapy in postmenopausal women, the design and use of selective estrogen receptor modulators (SERMs) has recently gained great attention and hope that some of these compounds will have beneficial effects on vascular and bone cells, without the detrimental side/toxic effects. The hypothesis is that, of a selected panel of potential SERMs, there will be a hierarchy of efficacy and toxicity, with regard to rapid induction of endothelial nitric oxide synthase (eNOS) activation through EC membrane ER46, and to proliferative responses of breast cancer cells, respectively. A compound that is found to be highly efficient at inducing eNOS activation, and minimally pro-proliferative, may be a tremendously useful prophylactic and threapeutic agent in humans.
Bibliographical Information:

Advisor:Jeffrey R. Bender MD

School:Yale University

School Location:USA - Connecticut

Source Type:Master's Thesis

Keywords:serms selective estrogen receptor modulators hormone replacement therapy postmenopause menopause coronary disease


Date of Publication:01/02/2007

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