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Estrogen Receptor Beta Is a Negative Regulator of Mammary Cell Proliferation Xiaozheng Song University of Vermont

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University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2014 Estrogen Receptor Beta Is A Negative Regulator Of Mammary Cell Proliferation Xiaozheng Song University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Animal Sciences Commons, and the Molecular Biology Commons Recommended Citation Song, Xiaozheng, "Estrogen Receptor Beta Is A Negative Regulator Of Mammary Cell Proliferation" (2014). Graduate College Dissertations and Theses. 259. https://scholarworks.uvm.edu/graddis/259 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. ESTROGEN RECEPTOR BETA IS A NEGATIVE REGULATOR OF MAMMARY CELL PROLIFERATION A Dissertation Presented by Xiaozheng Song to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Specializing in Animal Science October, 2014 Accepted by the Faculty of the Graduate College, The University of Vermont, in partial fulfillment of the requirements for the degree of Doctor of Philosophy, specializing in Animal Science. Dissertation Examination Committee: ____________________________________ Advisor Zhongzong Pan Ph.D. ____________________________________ Co-Advisor Andre-Denis Wright Ph.D. ____________________________________ Rona Delay, Ph.D. ____________________________________ David Kerr, Ph.D. ____________________________________ Chairperson Karen M. Lounsbury, Ph. D. ____________________________________ Dean, Graduate College Cynthia J. Forehand, Ph.D. Date: May 5, 2014 ABSTRACT The mammary gland cell growth and differentiation are under the control of both systemic hormones and locally produced growth factors. Among all these important hormones and growth factors, estrogen plays a central role in mammary gland development. The biological function of estrogen is mediated by estrogen receptor α (ERα) and estrogen receptor β (ERβ). Both ERα and ERβ are expressed in the mammary gland, but with distinct expression patterns. In the mammary gland, ERα has been proved to be the estrogen receptor that mediates the mitogenic function of estrogen. However the function of ERβ in mammary cell proliferation is less understood and there remains some controversy. Accumulating evidence indicates that ERβ, unlike ERα, is a negative regulator of mammary epithelial cell proliferation. In this dissertation, ERα and ERβ were evaluated for their expression patterns in the mammary gland. In the proestrus phase, ERα was detected in about 20% of mammary epithelial cells; in the diestrus phase, no ERα staining was detected in the mammary gland. ERβ was expressed in more than 50% of mammary epithelial cells and ERβ staining was detected in some stromal cells in the proestrus phase. In the diestrus phase, ERβ staining cells were very limited and the staining intensity was very weak. These data suggest that the expression levels of both ERα and ERβ undergo dynamic changes during the estrous cycle. In the ovariectomised (OVX) rats, both ERα and ERβ were detected in more than 50% of mammary epithelial cells. Compared with the ovary-intact rats, the mammary gland of the OVX rats showed more cells with ER expression, but the staining intensity was weaker. Taken together, the expression of ERα and ERβ is regulated by estrogen in normal mammary gland, while without estrogen stimulation in the OVX rats, more mammary cells showed ER expression, but at a lower level in these cells. The effects of ERα and ERβ on mammary cell proliferation were studied by two different approaches, activation of endogenous ERα and ERβ via selective agonists, and overexpression of ERα and ERβ via lentiviral infection. In the first approach, we used ERα and ERβ selective agonists, propylpyrazole-triol (PPT) and diarylpropionitrile (DPN) respectively, to activate endogenous ERα and ERβ in the OVX rats. We found that ERβ selective agonist DPN counteracts the proliferative effect of ERα selective agonist PPT in the mammary gland. In the second approach, ERα and ERβ were ectopically overexpressed in the mammary gland of mature virgin rats by lentivirus infection. We found that ERβ overexpression significantly decreased mammary cell proliferation rate in both the proestrus and diestrus phases, indicating that ERβ, unlike ERα, is a negative regulator for mammary cell proliferation. Collectively, these data supports that in contrast to ERα, ERβ activation or overexpression is able to inhibit mammary cell proliferation. CITATION Material from this dissertation has been published in the following form: Song, X. and Z.-Z. Pan.. (2012). "Estrogen receptor-beta agonist diarylpropionitrile counteracts the estrogenic activity of estrogen receptor-alpha agonist propylpyrazole-triol in the mammary gland of ovariectomized Sprague Dawley rats." The Journal of Steroid Biochemistry and Molecular Biology 130(1–2): 26-35. ii ACKNOWLEDGEMENTS First, I would like to express my deepest appreciation to my advisor Dr. Zhongzong Pan for all the support, encouragement, trust, effort and patience he had given me through my Ph.D. study. Without his detailed guidance and persistent help, I would not have been able to complete my work in this thesis. I would like to thank the rest of my thesis committee: Dr. Karen M. Lounsbury, Dr. Rona Delay, Dr. David Kerr for their scientific advice, insightful discussions and support over the past few years. A special thanks goes to Dr. Andre-Denis Wright for his support and guidance in the last year. I would like to thank the lab members I have worked with, Huining and Yili for their great comments and suggestions. I also appreciate all the help and advice I got from other faculty members and graduate students at the Department of Animal Science. I would like to especially thank the TA coordinator Frances Kinghorn and Jeffrey White for helping me to become a good teaching assistant. I also thank Janet Schwarz, the technician of the Microscopy Imaging Center, for teaching me how to use the microtome and microscopes and for technical suggestions. iii Finally, I would like to thank my family and friends for their endless love and caring. I especially thank my wife for being a true and great supporter and for standing by me with unconditional love over the past 11 years of my life. iv TABLE OF CONTENTS CITATION ........................................................................................................... ii ACKNOWLEDGEMENTS ................................................................................ iii LIST OF FIGURES ........................................................................................... xii CHAPTER 1: Introduction .................................................................................. 1 Estrogen ............................................................................................................... 1 Estrogen Biosynthesis ....................................................................................... 1 Estrogen Transport and Metabolism ................................................................. 3 Estrogen Receptors .............................................................................................. 4 The Discovery of Estrogen Receptors .............................................................. 4 The Structure of Estrogen Receptors ................................................................ 5 The Expression of Estrogen Receptors ............................................................. 7 The Coregulators of Estrogen Receptors .......................................................... 8 Coactivators .................................................................................................... 8 Corepressors ................................................................................................. 10 v Mechanisms of Estrogen Action ........................................................................ 11 Classical Ligand Dependent Pathway ............................................................ 11 Ligand Independent Pathway ......................................................................... 11 ERE Independent Pathway ............................................................................. 12 Nongenomic Pathway ..................................................................................... 13 Physiological Action of Estrogens ..................................................................... 14 Estrogen Action on the Ovary ........................................................................ 14 Estrogen Action on the Fallopian Tube .......................................................... 15 Estrogen Action on the Uterus ........................................................................ 16 Estrogen Action on the Cervix ....................................................................... 18 Estrogen Action on the Vagina ....................................................................... 18 Effect of Estrogen on the Menstrual Cycle..................................................... 20 Estrogen Action in the Male Reproductive System ........................................ 21 Estrogen Action in the Brain .........................................................................
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