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