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Dysregulation of Microrna Expression in Acquired Endocrine- Resistant Breast Cancer

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Dysregulation of Microrna Expression in Acquired Endocrine- Resistant Breast Cancer University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 12-2012 Dysregulation of microRNA expression in acquired endocrine- resistant breast cancer. Tissa Thomas Manavalan University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Recommended Citation Manavalan, Tissa Thomas, "Dysregulation of microRNA expression in acquired endocrine-resistant breast cancer." (2012). Electronic Theses and Dissertations. Paper 897. https://doi.org/10.18297/etd/897 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. DYSREGULATION OF MICRORNA EXPRESSION IN ACQUIRED ENDOCRINE-RESISTANT BREAST CANCER By Tissa Thomas Manavalan B.Sc., Bangalore University, 2005 M.Sc., Bangalore University, 2007 M.S., University of Louisville, 2011 A Dissertation Submitted to the faculty of the University of Louisville School of Medicine In Partial Fulfillments of the Requirements For the Degree of Doctor of Philosophy Department of Biochemistry and Molecular Biology University of Louisville, School of Medicine Louisville, KY December 2012 Copyright 2012 by Tissa Thomas Manavalan All rights reserved DYSREGULATION OF MICRORNA EXPRESSION IN ACQUIRED ENDOCRINE-RESISTANT BREAST CANCER By Tissa T. Manavalan B.Sc., Bangalore University, 2005 M.Sc., Bangalore University, 2007 M.S., University of Louisville, 2011 A Dissertation Approved on September 20, 2012 by the following Thesis Committee: Dr. Carolyn M. Klinge (Mentor) Dr. Barbara J. Clark Dr. Yong Li Dr. Robert A. Mitchell Dr. Theodore S. Kalbfleisch ii DEDICATION This dissertation is dedicated to my parents for their constant love, encouragement and support over the course of my life and my Ph.D. program. I would also like to dedicate this to my husband, Roshan James for his motivation that helped in the completion of my graduate studies. 111 ACKNOWLEDGEMENTS I am sincerely grateful to my mentor, Dr. Carolyn Klinge for her encouragement and support for the successful completion of my Ph.D. Her guidance was invaluable for my doctoral work. I would also like to convey my sincere thanks to my committee members, Dr. Barbara Clark, Dr. Y ong Li, Dr. Robert Mitchell and Dr. Ted Kalbfleisch for their valuable comments and advice towards the project. I would like to thank the members of the Klinge laboratory for their support and assistance over the years. A special thanks to Dr. Nalinie Wickramasinghe, a past member of the lab, for her guidance in the initial years of my Ph.D. iv ABSTRACT DYSREGULA nON OF MICRORNA EXPRESSION IN ACQUIRED ENDOCRINE-RESISTANT BREAST CANCER Tissa T. Manavalan September 20, 2012 MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level by repressing translation or stimulating mRNA degradation. In this study, I tested the hypothesis that miRNAs are differentially expressed in antiestrogen­ sensitive MCF-7 versus -resistant LY2 human breast cancer cells. Microarray analyses identified 97 miRNAs that are differentially expressed between two estrogen receptor alpha (ERa) -positive human breast cancer cell lines: endocrine-sensitive MCF-7 versus -resistant LY2 cells under basal conditions. Opposite expression of miRs-lOa, -21, -22, -12Sb, -181, -200a, -200b, -200c, -221, and -222 was confirmed between MCF-7 and LY2 cells. The ER antagonist ICI 182,780 (fulvestrant or Faslodex) generally blocked the effect of estradiol E2 and 4-hydroxytamoxifen (4- OHT) regulated miRs, i.e .. , miR-lOa, miR-21, miR-22, miR-200a, miR-221, and miR- 222, indicating that these responses in MCF-7 cells are ER-mediated. Time­ dependent variation in basal (ethanol, the vehicle), E2, and 4-0HT regulation of the top 8 miRNAs was detected in MCF-7 cells. Bioinformatic analyses to impute the biological significance of the identified miRNAs by identifying their computationally predicted target genes in the human genome using TargetScan, Pic Tar, and the Sanger v miRBase Targets databases was performed. Thirty six putative mRNA targets were identified. Agreement in the direction of anticipated regulation was detected for 12 putative targets. These miRNAs showing opposite expression between these two breast cancer cell lines may be involved in endocrine resistance. MiR-200 family includes two clusters i.e. miR-200 aJ200bl 429 and miR- 200cl141 encoded on chromosome 1 and chromosome 12, respectively. Lower miR- 200a, miR-200 band miR-200c expression was observed in estrogen-independent LCC1 and endocrine-resistant LCC2, LCC9, and LY2 compared to the parental, endocrine-sensitive MCF-7 human breast cancer cell line. ZEB 1 protein was found to be expressed in endocrine-resistant LY2 cells but not in endocrine-sensitive MCF-7 cells. LY2 cells did not express E-cadherin, a ZEB 1 target which is a marker for epithelial phenotype. This is the first demonstration that LY2 cells have undergone EMT as part of their endocrine-resistant phenotype. Concomitant with miR-200 decrease, there was an increase in ZEB 1 mRNA expressIOn m LY2 cells. Overexpression of miR-200b or miR-200c in LY2 cells changed the cellular morphology from a mesenchymal to an epithelial appearance and sensitized cells to inhibition by 4-0HT and fulvestrant. These studies indicate that reduced expression of miR-200 and a corresponding increase in ZEB 1 protein is an indicator of endocrine-resistance in breast cancer cells. vi TABLE OF CONTENTS DEDICA TION ............................................................................................................ iii ACKNOWLEDGEMENTS ....................................................................................... iv ABSTRACT .................................................................................................................. v TABLE OF CONTENTS .......................................................................................... vii LIST OF TABLES ....................................................................................................... x LIST OF FIGURES .................................................................................................... xi CHAPTER I: INTRODUCTION TO BREAST CANCER ..................................... 1 BREAST CANCER AND ESTROGEN SIGNALING ............................................................................ 1 ENDOCRINE THERAPIES FOR THE TREATMENT OF BREAST CANCER ................................... 3 MECHANISMS OF ENDOCRlNEITAMOXIFEN-RESISTANCE............................ ............................ 6 CHAPTER II: SIGNIFICANCE OF MICRO RNA EXPRESSION IN ENDOCRINEffAMOXIFEN -RESISTANT BREAST CANCER •..••..•....•..•..••••• 12 BIOGENESIS OF MICRORNA ......................................................................................................... 12 MICRORNA FUNCTION .................................................................................................................. 13 REGULATION OF MICRORNA EXPRESSION ............................................................................... 15 MICRORNA AS ONCOGENES OR TUMOR SUPPRESSORS ......................................................... 18 MICRORNA EXPRESSION IN BREAST CANCER ........................................................................... 19 MICRORNAs REGULATE ERaACTIVlTY ...................................................................................... 21 MICRORNA AND ENDOCRINE RESISTANCE ............................................................................... 23 DISSERTATION SPECIFIC AIMS AND HYPOTHESES .................................. 24 vii CHAPTER III: DIFFERENTIAL EXPRESSION OF MICRORNAs IN TAMOXIFEN- SENSITIVE MCF-7 VERSUS TAMOXIFEN-RESISTANT LY2 BREAST CANCER CELLS ..................................................................................... 27 1. INTRODUCTION .......................................................................................................................... 27 2. MATERIALS AND METHODS ...................................................................................................... 30 3. RESULTS AND DISCUSSION ...................................................................................................... 35 identification ofmiRNAs differentially expressed in MCF-7 and LY2 cells. ..................................... 35 Selection of endogenous control genes for Q-PCR normalization and validation of select miRNAs by Q-PCR ............................................................................................................................................... 46 Time course ofmiRNA expression in MCF-7 cells ............................................................................ 54 Time course of E2 and 4-0HT regulation of ERa, ERfJ, and Argonaute-2 (Ag02) ........................... 57 Computational identification ofmiRNA target mRNA genes in 4-0HT-treated MCF-7 cells ........... 60 PDCD4, BCL2, CYPIBI, and ERBB3 are differentially expressed in MCF-7 and LY2 cells ........... 63 ESRI and ERaprotein expression is lower in LY2 than MCF-7 cells .............................................. 67 miR-200-regulated ZEBI is reduced in LY2 cells .............................................................................
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