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Hormonal Activation of Genes Through Nongenomic HORMONAL ACTIVATION OF GENES THROUGH NONGENOMIC PATHWAYS BY ESTROGEN AND STRUCTURALLY DIVERSE ESTROGENIC COMPOUNDS A Dissertation by XIANGRONG LI Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 2005 Major Subject: Toxicology HORMONAL ACTIVATION OF GENES THROUGH NONGENOMIC PATHWAYS BY ESTROGEN AND STRUCTURALLY DIVERSE ESTROGENIC COMPOUNDS A Dissertation by XIANGRONG LI Submitted to Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved as to style and content by: _______________________________ _______________________________ Stephen H. Safe Weston W. Porter (Chair of Committee) (Member) _______________________________ _______________________________ Robert C. Burghardt Timothy D.Phillips (Member) (Chair of Toxicology Faculty) _______________________________ _______________________________ Kirby C. Donnelly Glen A. Laine (Member) (Head of Department) May 2005 Major Subject: Toxicology iii ABSTRACT Hormonal Activation of Genes through Nongenomic Pathways by Estrogen and Structurally Diverse Estrogenic Compounds. (May 2005) Xiangrong Li, B.S., Wuhan University Chair of Advisory Committee: Dr. Stephen H. Safe Lactate dehydrogenase A (LDHA) is hormonally regulated in rodents, and increased expression of LDHA is observed during mammary gland tumorigenesis. The mechanisms of hormonal regulation of LDHA were investigated in breast cancer cells using a series of deletion and mutant reporter constructs derived from the rat LDHA gene promoter. Results of transient transfection studies showed that the -92 to -37 region of the LDHA promoter was important for basal and estrogen-induced transactivation, and mutation of the consensus CRE motif (-48/-41) within this region resulted in significant loss of basal activity and hormone-responsiveness. Gel mobility shift assays using nuclear extracts from MCF-7 cells indicated that CREB family proteins interacted with the CRE. Studies with kinase inhibitors showed that estrogen- induced activation of this CRE was dependent on protein kinase C, and these data show that LDHA is induced through a nongenomic (extranuclear) pathway of estrogen action. Estrogen activates several nongenomic pathways in MCF-7 cells, and this study investigated the effects of structurally diverse estrogenic compounds on activation of mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), protein kinase A (PKA), and calcium/calmodulin-dependent protein kinase IV (CaMKIV). Activation of kinases was determined by specific substrate phosphorylation and transactivation assays that were diagnostic for individual kinases. The compounds investigated in this study include E2, diethylstilbestrol (DES), the phytoestrogen resveratrol, and the following synthetic xenoestrogens: bisphenol-A (BPA), nonylphenol, octylphenol, endosulfan, kepone, 2,2-bis(p-hydroxyphenyl)-1,1,1- trichloroethane (HPTE), and 2',3',4',5'-tetrachloro-4-biphenylol (HO-PCB-Cl4). With the iv exception of resveratrol, all the compounds activated PI3K and MAPK whereas activation of PKC by the xenoestrogens was structure-dependent and resveratrol, kepone and HO-PCB-Cl4 were inactive. Only minimal estrogen/xenoestrogen- dependent activation of PKA was observed. CaMKIV was activated only by E2 and DES, and HO-PCB-Cl4 was a potent inhibitor of CaMKIV-dependent activity. These results demonstrate that activation of nongenomic pathways by estrogenic compounds in MCF-7 cells is structure-dependent. v DEDICATION To my parents, Mingzhi Li and Jiayao Yu and my sister Ruohong Li vi ACKNOWLEDGMENTS First of all, I would like to thank my mentor, Dr. Stephen Safe, for his patience and guidance throughout my graduate career. I also wish to thank the other members of my committee: Dr. Robert Burghardt, Dr. Timothy Phillips, Dr. Kirby Donnelly, Dr. Weston Porter and Dr. Kenneth Ramos for their advice and support. I am grateful to my colleagues for their frendship and collaboration: Dr. Mark Wormke, Dr. Chunhua Qin, Dr. Renqin Duan, Dr. Matthew Stoner, Dr. Brad Saville, Dr. Thu Nguyen, and Dr. Fan Wang. I also like to thank Lorna Safe, Kim Daniel, and Kathy Mooney for their administrative help. vii TABLE OF CONTENTS Page ABSTRACT ................................................................................................................ iii DEDICATION ............................................................................................................. v ACKNOWLEDGMENTS ............................................................................................. vi TABLE OF CONTENTS ............................................................................................. vii LIST OF FIGURES ..................................................................................................... x LIST OF TABLES ....................................................................................................... xiii CHAPTER I INTRODUCTION ................................................................................. 1 1.1 Breast cancer................................................................................ 1 1.1.1 Incidence and mortality of breast cancer........................ 1 1.1.2 Classification of breast cancer ....................................... 2 1.1.2.1 Structure of the mammary gland ..................... 2 1.1.2.2 Clinical classification of breast cancer............. 3 1.1.2.3 TNM staging .................................................... 4 1.1.2.4 ER-positive and ER-negative cells .................. 5 1.1.3 Carcinogenesis............................................................... 6 1.1.4 Breast cancer risk factors............................................... 11 1.1.4.1 Age .................................................................. 11 1.1.4.2 Life time estrogen exposure ............................ 11 1.1.4.2.1 Estrogen promotes proliferation and suppresses apoptosis ....................... 12 1.1.4.2.2 Estrogen induces mutagenesis......... 15 1.1.4.2.3 Estrogen facilitates tumor invasion ... 15 1.1.4.2.4 Estrogen induces proliferation through paracrine pathways.............. 16 1.1.4.3 Lifestyle and environmental factors................. 16 1.1.4.4 Xenoestrogen hypothesis................................ 18 1.1.4.5 Genetic factors ................................................ 22 1.1.4.5.1 BRCA1.............................................. 22 1.1.4.5.2 BRCA2.............................................. 24 1.1.4.5.3 p53.................................................... 25 1.1.4.5.4 ATM .................................................. 27 1.1.4.5.5 PTEN ................................................ 28 1.1.4.5.6 STK11............................................... 28 1.1.5 Breast cancer treatment................................................. 29 1.1.5.1 Surgery and radiation ...................................... 30 1.1.5.2 Chemotherapy................................................. 31 viii CHAPTER Page 1.1.5.3 Endocrine therapy ........................................... 31 1.1.5.3.1 SERMs and antiestrogens ................ 31 1.1.5.3.2 Ovarian ablation and aromatase inhibitors............................................ 36 1.1.5.3.3 Progesterone .................................... 39 1.1.5.3.4 Estrogen therapy .............................. 39 1.1.5.3.5 Trastuzumab..................................... 40 1.2 Estrogen receptor ......................................................................... 40 1.2.1 The structure of estrogen receptor ................................ 40 1.2.2 The physiological functions of estrogen ......................... 43 1.2.2.1 Reproductive system and estrogen................. 43 1.2.2.2 Cardiovascular system and estrogen .............. 44 1.2.2.3 Bone and estrogen .......................................... 45 1.2.2.4 Nervous system and estrogen......................... 45 1.2.3 The genomic actions of estrogen receptor..................... 46 1.2.3.1 General transcription ....................................... 46 1.2.3.2 ER-mediated transcription............................... 49 1.2.3.3 Phosphorylation of estrogen receptor.............. 53 1.2.4 The nongenomic actions of estrogen receptor............... 54 1.2.4.1 Mitogen activated protein kinase (MAPK) ....... 54 1.2.4.2 Phosphatidylinositol 3- kinase (PI3K) .............. 58 1.2.4.3 Protein kinase A (PKA).................................... 63 1.2.4.4 Protein kinase C (PKC) ................................... 65 1.2.4.5 Calcium/calmodulin-dependent protein ........... kinase IV (CaMKIV) ......................................... 68 1.2.4.6 The nature of membrane associated estrogen-binding factor.................................... 72 1.3 Lactate dehydrogenase A (LDHA) ................................................ 74 1.4 Objectives ..................................................................................... 76 1.4.1 Identifying the E2-responsvie region of LDHA promoter .............................................................. 76 1.4.2 Identifying the mechanism of activation of CREB by estrogen ......................................................................... 77 1.4.3 Investigating the roles of ERα domains in kinase activation............................................................. 78 1.4.4 Investigating the roles of xenoestrogens in kinase activation............................................................
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