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THE ROLE of RELAXIN in PROSTATE CANCER by VANESSA

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THE ROLE of RELAXIN in PROSTATE CANCER by VANESSA THE ROLE OF RELAXIN IN PROSTATE CANCER by VANESSA CAMILLE THOMPSON B.Sc, The University of Victoria, 2001 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Genetics) THE UNIVERSITY OF BRITISH COLUMBIA July 2007 © Vanessa Camille Thompson, 2007 Abstract Prostate cancer is the leading cause of cancer in men, and there is currently a lack of novel treatment options for this disease. Relaxin, part of the insulin superfamily, is a potent peptide hormone normally produced and secreted by the human prostate. cDNA and tissue microarray analyses, indicated that relaxin is highly overexpressed in prostate cancer progression to androgen independence (Al), and is negatively regulated by androgens. Characterization of the relaxin receptor, LGR7, in xenografts and human patient tissue microarrays (TMAs) indicated that LGR7 is expressed in the stroma and epithelia, suggesting that relaxin may act in an autocrine and/or paracrine fashion. Relaxin is known to increase angiogenesis through upregulation of vascular endothelial growth factor, and matrix metalloproteases. To elucidate novel pathways that may be upregulated by relaxin in prostate cancer, the effects of relaxin overexpression in the LNCaP prostate cancer xenograft model were analysed by gene expression microarrays. A novel discovery is that the protocadherinY (PCDHY)/Wnt pathway is upregulated by relaxin, resulting in P-catenin translocation from the cell membrane to the cytoplasm and upregulation of Wntll, which can stimulate proliferation, transformation, and migration. Relaxin is well characterized in the uterus and ovary to increase insulin-like growth factor-I (IGF-I); relaxin may also increase IGF-I in prostate cancer. Since IGF-I and various other growth factor signaling is mediated by insulin receptor substrate-2 (IRS-2), and IGF-I signaling is important in prostate cancer progression to Al, we investigated the role of IRS-2 in LNCaP cells. IRS-2 mRNA is dramatically upregulated by androgens, and decreased by IGF-I in androgen treated cells. IRS-2 was knocked down using IRS-2 siRNA to explore the interaction between the IGF axis and androgen signalling. Combined IGF-I and androgen treatment reduced transcription of androgen regulated genes, n prostate specific antigen, insulin degrading enzyme, vascular endothelial growth factor, and clusterin. This indicates that in the presence of IGF-I treatment, IRS-2 mRNA is required for normal androgen mediated transcription. Due to the potential for relaxin to induce proliferation and metastases, and the necessity of IRS-2 to mediate androgen action, relaxin and IRS-2 are intriguing targets for novel, targeted therapeutics for prostate cancer. in Table of Contents Abstract ii Table of Contents iv List of Tables vi List of Figures vii List of Abbreviations ix Acknowledgements xi Dedication xii Co-Authorship Statement xiii Chapter 1. Introduction 1 1.1 The Prostate 1 1.2 Relaxin 9 1.3 Hypothesis 24 1.4 Objectives 24 1.5 References 26 Chapter 2. Relaxin Becomes Upregulated During Prostate Cancer Progression to Androgen Independence and is Negatively Regulated by Androgens 40 2.1 Introduction 40 2.2 Materials and Methods 43 2.3 Results 50 2.4 Discussion 59 2.5 References 66 Chapter 3. Relaxin Drives Wnt Signalling Through Upregulation of PCDHY in Prostate Cancer 71 3.1 Introduction 71 iv 3.2 Materials and Methods 74 3.3 Results 80 3.4 Discussion 92 3.5 References 98 Chapter 4. Suppression of Androgen Signaling by IGF-I due to siRNA Depletion of IRS-2 102 4.1 Introduction 102 4.2 Materials and methods 104 4.3 Results 107 4.4 Discussion 117 4.5 References 121 Chapter 5. Discussion 125 5.1 Relaxin regulation in prostate cancer progression 125 5.2 Relaxin regulated Wntl 1 pathway 127 5.3 IRS-2 mediates androgen regulated gene expression 130 5.4 Future Directions 132 5.5 References 136 Appendix I. Genes upregulated at least 5-fold in Rl 881-treated cells 139 Appendix II. Genes downregulated at least 5-fold in Rl 881-treated cells 140 Appendix III. University of British Columbia Animal Care Certificate 141 Appendix IV. Primers for quantitative RT-PCR 142 v List of Tables Table 3.1 List of Figures Figure 1.1 Histologic grades of prostate adenocarcinoma 4 Figure 1.2 LHRH axis for anti-androgen therapy 6 Figure 1.3 Relaxin structure 12 Figure 1.4 Schematic of LGR7 tertiary structure 13 Figure 1.5 Relaxin signaling pathways used by the relaxin receptor, LGR7 in multiple cell types 15 Figure 2.1 Relaxin levels in LNCaP cells decrease with increased androgen concentration 52 Figure 2.2 Relaxin levels in LNCaP cells decrease with increased duration of androgen treatment 53 Figure 2.3 Relaxin mRNA levels increase with progression to androgen independence in LNCaP subcutaneous xenograft model in nude mice 56 Figure 2.4 Relaxin levels increase in human prostate cancer tissue with increased duration of neoadjuvant hormone therapy (NHT) 58 Figure 3.1 Relaxin is overexpressed in LNCaP-RLX stable cell lines 81 Figure 3.2 Relaxin and LGR7 protein levels are higher in LNCaP-RLX xenografts grown in intact mice compared to controls, using IHC 82 Figure 3.3 LGR7 is expressed in malignant epithelium and stromal cells of prostate. 84 Figure 3.4 LNCaP-RLX xenograft tumours grow more rapidly than LNCaP-GFP xenografts in intact mice 86 Figure 3.5 Wntll staining is increased after six months NHT, and sustained in Al metastases in human patient samples 90 vii Figure 3.6 Relaxin overexpression causes p-catenin to translocate to the cytoplasm in intact mice 91 Figure 3.7 Model of relaxin driving upregulation of PCDHY, with P-catenin translocating to the cytoplasm, and downstream upregulation of Wntl 1 96 Figure 4.1 IGF-I treatment reduces IRS-2 mRNA levels 109 Figure 4.2 AR siRNA knocks down AR mRNA and abrogates androgen mediated transcription of PSA and IRS-2 110 Figure 4.3 IRS-2 siRNA dose curve 112 Figure 4.4 IRS-2 is required for androgen mediated transcription in the presence of R1881 and IGF-I 113 Figure 4.5 Effect of IRS-2 siRNA on AR and IGF signaling molecules 116 viii List of Abbreviations Al androgen independence AR androgen receptor ATBF1 at-binding transcription factor 1 Bcl-2 B-cell CLL/lymphoma 2 bHLH class B basic helix-loop-helix cAMP cyclic AMP C02 carbon dioxide CREB cAMP response element binding protein CSS charcoal stripped serum DHT dihydrotestosterone DRE digital rectal exam EGF epidermal growth factor ERK extracellular signal-regulated kinase FCS fetal calf serum FOXO forkhead box 0 FSH follicle stimulating hormone GFP green fluorescent protein GnRH gonadotrope releasing hormone GPR G protein coupled receptor GST glutathione-S-transferase IDE insulin degrading enzyme IGF insulin-like growth factor IGFBP IGF binding protein IGF-IR insulin-like growth factor receptor type I IHC immunohistochemistry INSL insulin-like peptides IRES internal ribosome entry site IRS insulin receptor substrate KGF keratinocyte growth factor KLK kallikrein LGR7 relaxin receptor LGR8 INSL3 receptor LH luteinizing hormone LHRH luteinizing hormone releasing hormone LNCaP- GFP LNCaP xenografts stably transfected with empty vecot control LNCaP- RLX LNCaP xenografts stably overexpressing relaxin M metastasis MAPK mitogen activated protein kinase MEK MAPK/ERK kinase MMP matrix metalloprotease N lymph node NHT neadjuvant hormone therapy NO nitric oxide NOS nitric oxide synthase ODC ornithine decarboxylase PCDH protocadherin PCR polymerase chain reaction PI3K PI3 kinase PIN prostatic intraepithelial neoplasia PKA protein kinase A PKC protein kinase C PSA prostate specific antigen PTEN phosphatase and tensin homolog Q-PCR semi-quantitative real time - PCR relaxin relaxin H2 RLX relaxin RTK receptor tyrosine kinase s.c. sub cutaneous SF serum free siRNA short interfering RNA SRC steroid receptor coactivator SRE sterol response element SREBP sterol response element-binding protein STAT signal transducer and activator of transcription T tumor growth T-cell factor and lymphoid enhancer factor family of TCF/LEF1 transcription factors TFE transcription factor for immunoglobulin heavy-chain enhancer TIMP tissue inhibitors of metalloprotease TMA tissue microarray TNM tumor, node, metastasis TRAMP transgenic adenocarcinoma of mouse prostate UV ultraviolet VEGF vascular endothelial growth factor Wnt wingless-type MMTV integration site family x Acknowledgements My experience as a PhD student has been made more enjoyable and fulfilling by many people. I would like to acknowledge the friends and colleagues who have helped along the way. John Cavanagh and Robert Shukin are two great friends whose expertise and insight have been invaluable along the way. My fellow graduate students have inspired me and kept me sane. I would like to thank Dr. Dawn Cochrane, Dr. Lindsay Brown, Leah Prentice, and Melanie Lehman for all their feedback and support. Dr. Susan Moore and Dr. Tanya Day have been extremely generous with their assistance. I would like to thank my supervisor, Dr. Colleen Nelson, for her guidance, encouragement, and motivation. xi Dedication To my husband, Cory Wood. Your love and support throughout this process have been immeasurable. Co-Authorship Statement The work presented in this thesis was conducted under the guidance of my supervisor, Dr. Colleen Nelson, and is due to collaboration with several individual researchers. The specifics of each researcher's involvement are detailed below. Chapter 2. Tanis Morris performed the xenograft experiment, and contributed the northern blot, Ladan Fazli stained the tissue microarrays and scored them for staining intensity, John Cavanagh developed the antibody against relaxin, Tatyana Hamilton designed the relaxin Q-PCR primers and probes. Chapter 3. Antonio Hurtado-Coll photomicrographed tissue microarrays and managed automated analysis software, Dmitry Turbin scored for subcellular P-catenin localization in xenograft tissue microarrays, Ladan Fazli manually scored all remaining tissue microarrays. Chapter 4.
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