Nuclear Receptors in Human Health and Disease

Introduction
Nuclear Receptors: The Past, the Present and the Future
Overview
Contents
Part I: Reproduction and Development
1: Nuclear Receptors in Pregnancy and Outcomes: Clinical Perspective
1.1 Introduction
1.2 The Role of Nuclear Receptors in Maintaining a Healthy Pregnancy
1.2.1 Progesterone Receptors and PPARS in Early Pregnancy
1.2.2 Liver-X-Receptors, Clock Genes and Maternal Metabolic Adaptations in Mid-to-Late Pregnancy
1.2.3 Parturition
1.3 Nuclear Receptors and Gestational Disorders
1.3.1 Gestational Diabetes Mellitus
1.3.2 Intrahepatic Cholestasis of Pregnancy
1.3.3 Pre-eclampsia
1.3.4 Spontaneous Preterm Labour
1.4 Conclusions
References
2: Female Reproductive Systems: Hormone Dependence and Receptor Expression
2.1 Introduction
2.2 Anatomy of the Female Reproductive System
2.2.1 Ovaries
2.2.2 Fallopian Tubes
2.2.3 Uterus
2.2.4 Cervix and Vagina
2.3 Hormone Biosynthesis and Metabolism Within the Female Reproductive System
2.3.1 Endocrine – Ovary
2.3.2 Intracrine
2.4 Expression and Action of Steroid Receptors Within the Female Reproductive System
2.4.1 Oestrogen Receptors
2.4.2 Progesterone Receptors
2.4.3 Androgen Receptor
2.5 Summary and Future Prospects
References
3: Nuclear Receptors in Ovarian Function
3.1 Introduction
3.2 Hormonal Control of Dynamic Physiological Change in the Ovary
3.3 Physiological Effects of Nuclear Hormone Receptors on Ovarian Functions
3.4 Signalling Mechanism of Nuclear Receptors in the Ovary
3.5 Conclusions
References
Part II: Metabolism
4: Nuclear Receptors in Energy Metabolism
4.1 Introduction and Outline
4.2 Liver
4.2.1 PPARα Is the Key to Liver Lipid Metabolism
4.2.2 LXR and FXR Are Regulators of Cholesterol Metabolism
4.2.3 GR – Linking Inflammation and Metabolism
4.3 Adipose Tissue
4.3.1 PPARγ Is the Master Regulator of Adipose Tissue Function
4.4 Muscle
4.4.1 PPARβ/δ – Regulator of Skeletal Muscle
4.5 Pancreas
4.5.1 The NR4A Family of Orphan Nuclear Receptors as Regulators of β-Cell Physiology
4.6 Conclusion
References
5: Nuclear Receptors and Lipid Sensing
5.1 The Molecular Biology of Lipid-Sensing Nuclear Receptors
5.1.1 Liver x Receptors (NR1H2, NR1H3)
5.1.1.1 Structure of the LXRs
5.1.1.2 Endogenous Selective Modulators of LXR
5.1.1.3 Fine-Tuning of LXR Signaling
5.1.2 Farnesoid x Receptor Alpha (NR1H4)
5.1.2.1 Structure of FXR
5.1.2.2 FXR Ligands
5.1.2.3 Fine-Tuning of FXR Signaling
5.1.3 Peroxisome Proliferator-Activated Receptors (NR1C1, NR1C2, NR1C3)
5.1.3.1 Structure of PPARs
5.1.3.2 PPAR Ligands
5.1.3.3 Fine-Tuning of PPAR Signaling
5.1.4 Other Lipid-Sensing NR
5.2 Emerging Trends for Lipid-Sensing Nuclear Receptors
5.2.1 Cancer Theranostics
5.2.1.1 LXR in Breast and Prostate Cancer
5.2.1.2 FXR in Cancer
5.2.1.3 PPAR in Cancer
5.2.2 Lipid-Sensing Nuclear Receptors and Immuno-Oncology
5.2.3 Therapeutic ligands Targeting Lipid-Sensing Nuclear Receptors
5.3 Perspectives
References
Part III: Central Systems
6: Corticosteroid Receptors in Cardiac Health and Disease
6.1 Introduction
6.2 MR and Heart Failure
6.3 GR Limits Cardiac Injury and Subsequent Pathophysiology
6.4 Glucocorticoid Action in Heart Is Sexually Dimorphic
6.5 Cardiac Injury and Repair: The Balance of GR and MR Action as a Determinant of Cell Death or Survival
6.6 Glucocorticoids Regulate calcium Handling and Metabolism in Cardiomyocytes
6.7 Early Life Programming of Cardiovascular Disease: Creating Vulnerability?
6.8 Concluding Remarks and Future Perspectives
References
7: Physiological Convergence and Antagonism Between GR and PPARγ in Inflammation and Metabolism
7.1 Introduction
7.2 GR and PPARγ in Monocytes and Macrophages
7.3 GR and PPARγ in Non-Macrophage Immune Cell Subsets
7.3.1 T Cells
7.3.2 Dendritic Cells (DCs)
7.4 GR and PPARγ in Adipocytes
7.5 GR and PPARγ in the Liver
7.6 Concluding Remarks
References
8: Circadian Rhythm and Nuclear Receptors
8.1 Ligands and NR Expression Through Time
8.2 Circadian Clocks
8.2.1 Clocks, Entrainment and Misalignment
8.3 Nuclear Receptors Within the Clock
8.4 Circadian Impacts of NHR Function
8.5 Nuclear Hormone Receptor Chronotherapeutics
8.6 Conclusions
References
9: Vitamin D and Gut Health
9.1 Introduction
9.2 Classical Role of Vitamin D as a Regulator of Intestinal Ca Absorption
9.3 Gut Absorption and Excretion of Vitamin D
9.4 Cellular Targets of Vitamin D Action in the Intestine
9.5 Conclusions
References
Part IV: Cancer
10: Estrogen Receptor Alpha and ESR1 Mutations in Breast Cancer
10.1 Introduction to Estrogen Receptor
10.1.1 Structure
10.1.2 Functional Domains
10.1.3 Genomic Signaling
10.1.4 Estrogen Response Elements and Gene Regulation
10.1.5 Normal Physiologic Functions and Tissue Expression
10.2 Wild-Type ERα in Breast Cancer
10.2.1 Prognostic and Predictive Implications
10.2.2 Molecular Subtypes or Heterogeneity in ER Positive
10.2.3 Evidence for Tumorigenic Signaling
10.2.4 Ligand-Independent Activation Through Phosphorylation
10.2.5 Downstream Redirection via Transcription Factors
10.3 Endocrine Treatment & Resistance in Breast Cancer
10.3.1 Overview of Therapies Targeting ER
10.3.2 Mechanisms of Endocrine Resistance
10.4 ESR1 Mutations in Breast Cancer
10.4.1 Types of Genomic Alterations
10.4.2 ESR1 Ligand Binding Domain Mutations
10.4.3 Endocrine Resistance and Cellular Phenotypes
10.4.4 cfDNA Analysis of Clinical Trials
10.4.5 Preclinical Evaluation of Therapeutic Vulnerabilities
10.4.6 Future Directions for Treatment
References
11: AR Structural Variants and Prostate Cancer
11.1 The Androgen Receptor and Its Role in Prostate Cancer
11.2 Discovery of the AR-Vs
11.3 Regulation of AR-V Expression
11.4 Biological Activity and Function of AR-Vs
11.5 AR-V Prevalence and Significance in Disease
11.6 Therapeutically Targeting AR-Vs
11.7 Inhibition of the AR N-Terminal Domain
11.8 Inhibition of the AR-DBD
11.9 Degradation of AR
11.10 Concluding Remarks
References
12: ERβ and Inflammation
12.1 Colon Inflammation and Colorectal Cancer
12.1.1 Pro-Inflammatory Signaling
12.2 Estrogen Signaling in Colon Inflammation and CAC
12.3 Expression Pattern and Role of ERβ in Colon
12.3.1 Intestinal Epithelial ERβ Regulates Core Clock Genes
12.3.2 Intestinal Epithelial ERβ Regulates NFκB Signaling and Gut Microbiota
12.4 Concluding Remarks
References
13: Genomic Insights into Non-steroidal Nuclear Receptors in Prostate and Breast Cancer
13.1 Nuclear Receptor Genomic Interactions Are Highly Integrated and Sense a Wide Variety of Inputs
13.2 Genomic Interactions of Non-steroidal Nuclear Receptors in PCa and BrCa
13.2.1 The Vitamin D Receptor
13.2.2 Retinoic Acid Receptors
13.2.3 RAR Related Orphan Receptor C
13.2.4 Peroxisome Proliferator-Activated Receptors
13.2.5 Hepatocyte Nuclear Factor 4 α and γ
13.2.6 COUP Transcription Factor I and II
13.2.7 NUR77
13.3 Mechanisms of NR Cooperation: Bookmarking Functions by Non-steroidal NRs
13.4 Genomic Approaches to Defining Type I and II NR Cistromes and Interactions
13.5 Conclusion
References
Part V: New Developments in Transcriptional Control by Nuclear Receptors
14: Protein Condensation in the Nuclear Receptor Family; Implications for Transcriptional Output
14.1 The Nuclear Receptor Superfamily
14.2 A Condensate Model for NR Transcriptional Regulation
14.3 Evidence of NR Condensate Formation
14.4 Potential Condensate Formation of the NR Superfamily
14.5 Conclusion and Future Perspectives
References
15: Prostate Cancer Epigenetic Plasticity and Enhancer Heterogeneity: Molecular Causes, Consequences and Clinical Implications
15.1 Introduction
15.2 Prostate Cancer as Enhancer-Driven Disease
15.3 AR Biology and Enhancer Regulation in Prostate Cancer
15.4 PCa-Specific Pioneer Factors as Source of Regulatory Heterogeneity in AR Binding
15.5 AR Cistromes are Heterogeneous Between Different Tissue, Cellular and Tumor Contexts
15.6 AR Cistromic Heterogeneity Progressively Develops from PCa Initiation to Neuroendocrine Differentiation
15.7 Metastatic PCa Heterogeneity
15.8 Non-coding and Protein Coding Somatic Mutations Induce AR Cistromic Heterogeneity
15.9 Risk SNPs and Somatic Mutations are Enriched at AR-Bound Enhancers
15.10 Clinical Implications and Biomarker Development of Heterogeneity in Epigenetic Subtypes
15.11 Future Outlook
References
16: Epigenetic Coregulation of Androgen Receptor Signaling
16.1 Introduction
16.2 AR Structure and Coregulator Binding Interactions
16.3 AR-Coregulator Mediated Alteration of the Chromatin Landscape
16.3.1 Pioneer Factors
16.3.2 Nucleosome Remodellers
16.3.3 Histone Post-translational Modifiers
16.3.3.1 Histone Acetylases/Deacetylases
16.3.3.2 Histone Methylases/Demethylases
16.3.4 Epigenetic Readers
16.3.5 Chromatin Looping
16.4 Dysregulated Expression and Function of Coregulators Promotes PCa Progression by Multiple Mechanisms
16.5 Therapeutic Targeting of AR Epigenetic Coregulators
16.6 Conclusion
References
Part VI: Clinical Translation
17: Clinical Translation: Targeting the Estrogen Receptor
17.1 Looking Back: The Beginnings of Endocrine Targeting
17.2 The Advent of Small Molecule Modulators of ER Function
17.3 Alternative Strategies for Endocrine Suppression: Targeting the Ligand
17.4 In Pursuit of a Pure Antiestrogen
17.4.1 Prospective Optimization of ERα Degradation: Contemporary SERD/SERM Hybrids
17.4.2 Latest Generation ER Antagonists: The -Esterants
17.5 Novel Approaches to ER Antagonists: Heterobifunctional Degraders and Covalent Binders
17.6 Bringing It Back to the Biology: Neoadjuvant Studies as Potentially Valuable Testing Grounds
17.7 Outlook
References
18: Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors
18.1 Introduction
18.2 Modular Structure of Nuclear Hormone Receptors
18.2.1 Intrinsically Disordered N-terminal Domain (NTD)
18.2.2 DNA-Binding Domain (DBD) and Hinge Region
18.2.3 Ligand-Binding Domain (LBD)
18.3 Androgen Receptor
18.4 Rationale for Developing Inhibitors to the NTD
18.5 Small Molecule Inhibitors of AR-NTD
18.6 First-in-Human Clinical Trials
18.7 Conclusions
References
19: Genetic Variation and Mendelian Randomization Approaches
19.1 Introduction
19.1.1 GWAS on NR Levels
19.1.2 25 Hydroxyvitamin D (Calcidiol)
19.1.3 Thyroid Hormones (Thyroxin and Triiodothyronine)
19.1.4 Estradiol
19.1.5 Testosterone and its Precursors
19.1.6 Vitamin A
19.1.7 Cortisol
19.2 Discussion
19.2.1 Missing Heritability
19.2.2 Ethnic Representation
19.2.3 Limited Access to Measurements of Direct Ligands of NR
19.2.4 Functional Follow-Up
19.2.5 Future Clinical Applications
References
Index