Prostate Cancer: Cellular and Genetic Mechanisms of Disease Development and Progression (Advances in Experimental Medicine and Biology, 1210)

Preface
Contents
Contributors
Diet and Lifestyle in Prostate Cancer
	The Impact of PSA Screening on Epidemiological Studies of Prostate Cancer
	Dietary Factors and Prostate Cancer Risk and Survival
		Fat Intake
		Meat Intake
		Fish Intake and Marine Fatty Acids
		Dairy Products and Calcium
		Vitamin D
		Lycopene and Tomatoes
		Soy/Phytoestrogens
		Vitamin E and Alpha-tocopherol
		Selenium
	Other Lifestyle Factors
		Tobacco
		Obesity
		Body Size in Early Life
		Weight Change
	Physical Activity
	Summary and Future Directions
	References
Dietary Carcinogens and DNA Adducts in Prostate Cancer
	Introduction
	The Diet as a Risk Factor for Human PC
		High-Fat Diet
		Fatty Acids
		Inflammation
		Oxidative Stress
		Dairy Products
		Saturated Fat Intake
		High-Calcium Intake
		Vitamin D
		IGF-1
		Alcohol
		Red and Processed Meat
		Heme Iron
		N-Nitroso Compounds (NOCs)
		Polycyclic Aromatic Hydrocarbons (PAHs)
	Heterocyclic Aromatic Amines (HAAs) and PC
		HAA Formation and Sources of Exposure
		Bioactivation and Formation of DNA Adducts
		Carcinogenesis of HAAs
	PhIP DNA Damage, Mutation, and Carcinogenicity in Prostate
		Rodent Studies
		Human Studies
	Conclusion
	References
Genetic, Environmental, and Nuclear Factors Governing Genomic Rearrangements
	Introduction
	Formation of DNA Double Strand Breaks (DSBs)
		Cellular Stressors
			Genotoxic Stress
			Oxidative Stress
			Topological Stress
			Interplay Between Cellular Stressors
		DNA Sequence and Epigenetic Features
	Mis-Repair of DNA DSBs
		Spatial Proximity
		Error-Prone End-Joining and the Formation of Genomic Rearrangements
		Novel Mediators of ETS Gene Rearrangements
		The Formation of Complex Genomic Rearrangements by Chromoplexy
	Conclusions and Future Directions
	References
Cells of Origin for Prostate Cancer
	Definition of Cells of Origin for Cancer
	Significance of Investigating Cells of Origin for Cancer
	Epithelial Cell Lineages in Normal Human and Rodent Prostates
	Developmental Origin of Prostate Epithelial Cells
	Inter-lineage Hierarchy in Normal Prostate Epithelium in Adults
		Basal Stem/Progenitor Cell Theory
		Luminal Stem/Progenitor Cell Theory
		Independent Lineage Theory and Intra-lineage Heterogeneity
			Basal Cell Heterogeneity
			Luminal Cell Heterogeneity
			Neuroendocrine Cell Heterogeneity
			Heterogeneity Associated with Anatomy
	Lineage Plasticity Under Conditions of Stress
	Cells of Origin for Prostate Cancer
		Histological Variants of Prostate Carcinoma
		Correlative Evidence for the Identity of Cells of Origin for Prostate Cancer
		Both the Basal and Luminal Cells Can Serve as Targets for Transformation
		Preferred or More Efficient Target for Transformation, Basal or Luminal Cells?
		Cells of Origin for Aggressive Prostate Cancer
	Summary and Future Directions
	References
Prostate Cancer Genomic Subtypes
	The Challenges of (Prostate) Cancer Genome Analysis
	The Prostate Cancer Genome
		The Somatic Molecular Landscape of Localized Prostate Cancer
		Hallmarks of Prostate Cancer Genomes
			Single Nucleotide Variation
			Structural Variation
			Genomic Rearrangements
			Chromoplexy
			Copy Number Aberrations
			Chromothripsis
			The DNA Damage Response
	Tumor Evolution and the Impact of Somatic Genome Heterogeneity
		Multifocality
		Sub-clonal Reconstruction of Localized Prostate Cancer
	Familial Prostate Cancer and Germline-Somatic Interactions
		Germline Variation and Prostate Cancer Risk
		Germline-Somatic Interaction: BRCA2
	Clinico-Genomics
		Prognostic Biomarkers: CNAs and Percentage of the Genome Altered
		Prognostic Biomarkers: Impact of Multi-modal Profiling
		Challenges for Implementation of Molecular Biomarkers
		Heterogeneity
	Conclusions
	References
Prostate Cancer Transcriptomic Subtypes
	Overview of Transcriptomics
	Technology
	Methods of Subtyping
	Subtypes
		Capture Genomic Subtypes
		Unsupervised Hierarchical Clustering
		Supervised Clustering to Capture Specific Biologic Characteristics
		Subtypes Developed for Prognosis
			Commercial Classifiers
			Non-commercial Classifiers
		Subtypes Developed for Predicting Treatment Response
	Conclusions
	References
Immunological Complexity of the Prostate Cancer Microenvironment Influences the Response to Immunotherapy
	Introduction
	CD8+ T cells in Cancer
	Immune Response to Viruses
		Danger Sensing
		Antigen Presentation
		Lymphoid Organization in Viral Infections
		CD8+ T cell Effector Function
	The Immune Response to Cancer
		Danger Sensing in Tumors
		Antigen Presentation of Tumor Antigens
		DCs in Cancer
		Lymphoid Organization in Tumors
		Macrophages in Cancer
	CD8+ T cells in Cancer
		LCMV Model of CD8+ T cell Exhaustion
	Stem-Like Model of CD8+ T cell Exhaustion
	Prostate Cancer Tumor-Associated Antigens
		Prostate-Specific Antigen
		Prostate Acid Phosphatase
		Prostate-Specific Membrane Antigen
		Prostate Stem Cell Antigen
		Mucin-1
		NY-ESO-1
		T-cell Receptor Alternate Reading Frame Protein
		GRB2-Like Endophilin B2
		Six Transmembrane Epithelial Antigen of the Prostate 1
	Models of Murine Prostate Cancer
		TRAMP
		LADY
		c-Myc Models
		PTEN Knockout
	Prostate Cancer Immunotherapy: Vaccines, Checkpoint Blockade, and Combination Therapy
		Vaccines
		CTLA-4 Blockade
		PD-1/PD-L1 Blockade
		Other Therapies
	Conclusions
	References
The Tumor Microenvironments of Lethal Prostate Cancer
	Introduction
	The Muscle Stroma and Pseudo-Capsule
	Hypoxia in PCa Invasion and Metastasis
		Angiogenesis
		Epithelial-Mesenchymal Transition
		Extracellular Matrix Degradation
		Extracellular Matrix Remodeling
	Perineural Invasion
	Extracellular Vesicles: A Focus on Microvesicles in PCa
	Summary
	References
The Bone Microenvironment in Prostate Cancer Metastasis
	The Bone Marrow Microenvironment
	Hematopoietic Niche, Colonization and Dormancy
	Osteoclasts and the Vicious-Cycle
	Cooperativity and AR Heterogeneity Among Metastatic Cells
	Concluding Remarks
	References
Prostate Cancer Energetics and Biosynthesis
	Introduction
	Metabolic Reprogramming in Prostate Cancer
		Glucose Metabolism
		Lipid Metabolism
		Amino Acid Metabolism
		Hexosamine Biosynthetic Pathway
		Metabolic Scavenging
	Regulation of Metabolic Reprogramming
		Signal Transduction
		Non-coding RNAs
		Influence of the Tumor Microenvironment
	Exploiting Metabolic Alterations for Prostate Cancer Therapy
		Diagnostic Imaging of Prostate Cancer
		Hyperpolarized Imaging in Prostate Cancer
		Preclinical Hyperpolarized Metabolic Imaging in Prostate Cancer
		Clinical Hyperpolarized Metabolic Imaging in Prostate Cancer
		Challenges of Clinical Translation of Hyperpolarized Metabolic Imaging
		PET Imaging in Prostate Cancer
		Biofluid and Tissue Metabolite Biomarkers
		Drug Development
	Conclusions and Future Directions
	References
Canonical and Noncanonical Androgen Metabolism and Activity
	Introduction
	Residual Prostate Tumor Androgens in the Progression of CRPC
	Pathways of Androgen Biosynthesis
		Androgen Biosynthesis in the Adrenal Gland and Peripheral Tissues
		Androgen Biosynthesis in the Prostate and Pre-receptor Control of DHT Metabolism
		Classical, Backdoor and 5α-Dione Pathways of Androgen Metabolism
	Altered Expression of Steroidogenic Enzymes in Progression to CRPC
		Altered Expression of Steroidogenic Genes in Primary Prostate Cancer
		Altered Expression of Steroidogenic Genes in Castration Resistant Prostate Tumors
		Alternative Splicing of Androgen Metabolizing Enzymes in Prostate Cancer
	Functional Evidence of Intracrine Steroidogenesis in Prostate Cancer
		Evaluation of Steroidogenesis in Normal Prostate and Prostate Cancer Tissue
		Experimental Models of De Novo Steroidogenesis in CRPC
		Drivers of Intratumoral Androgen Biosynthesis
		Impact of Stromal Cells and the Bone Microenvironment on Intratumoral Androgen Concentrations
	Noncanonical Androgens as Unrecognized Drivers of Prostate Cancer Progression
		Circulating Levels of Non-canonical 11-Oxygenated Androgens
		Activation of Wild-Type AR by 11-Oxygenated Derivatives of Adrenal Steroids
		Contribution of 11-Oxygenated Androgens to the Androgen Pool in CRPC
		Altered Sensitivity of 11-Oxygenated Steroids to Activation by AKR1C3 and Inactivation by UGT2B Enzymes
	Inhibition of Steroidogenesis in CRPC
		Mechanisms of Response and Resistance to Inhibition of CYP17A1
		Metabolism of Abiraterone by Steroidogenic Enzymes and Implications for Treatment
		Targeting Steroid Sulphatase
		Targeting HSD11B2 and CYP11B1, Enzymes Unique to the Generation of 11-Oxygenated Androgens
		Targeting AKR1C3
	Precision Predictors of Response to Abiraterone
		Germline Variation in SLCO Transport Genes
		Germline Variation in HSD3B1
	Noncanonical Role for Steroid Metabolizing Enzymes in Prostate Cancer Progression
	Conclusions
	References
Germline and Somatic Defects in DNA Repair Pathways in Prostate Cancer
	The DNA Damage Repair Machinery: An Overview
	The Landscape of DNA Repair Gene Alterations in Prostate Cancer
		Genomic Alterations in Prostate Cancer
		Genomic Landscape of Localized Prostate Cancer
		Genomic Landscape of Advanced Prostate Cancer
	Germline Mutations in DNA Repair Genes: Prevalence and Implications
		MMR Germline Mutations: Lynch Syndrome
	Impact of DNA Repair Defects in Clinical Outcome for Prostate Cancer
	Clinical Development of PARP Inhibitors in Prostate Cancer
	Targeting DNA Repair Beyond PARP1
		Platinum-Based Chemotherapy
		Other Inhibitors of DDR Proteins
	Immunotherapy for Prostate Cancer and MMR Defects
	Practical Aspects and Challenges to Stratify Patients Based on DNA Repair Defects
	Conclusions
	References
The Role of RB in Prostate Cancer Progression
	Introduction
	Structure and Classical Cell Cycle Functions of RB
		The RB-Pathway
		The RB Family
		RB and the Cell Cycle
		The Role of RB Regulation of the Cell Cycle in Prostate Cancer
		Complex Relationship Between RB and the Androgen Receptor
			AR as a Transcriptional Target of RB/E2F
			RB as a Cofactor to AR
			Interactions Between E2F and AR
	The Role of RB-E2F Non-cell Cycle Functions in Prostate Cancer
		RB and Apoptosis
		RB and Senescence
		RB and Metastasis
		RB and Metabolism
	The Role of RB in Cellular Identity and Differentiation Status
		RB-E2F Represses Transcription of Pluripotent Networks
		RB and Chromatin Modifiers
			RB-PRC2
		Epigenetic Role of RB in Therapy Response
	Emerging Functions of RB
		RB and Genome Stability
		Cancer Immunity
		RB as a Biomarker
	Conclusions and Perspectives
	References
Interplay Among PI3K/AKT, PTEN/FOXO and AR Signaling in Prostate Cancer
	Introduction
	Activation of PI3K Due to PTEN Genetic Alterations
		PTEN Mutations Account for the Major Cause of PI3K Activation in Prostate Cancer
		Pten Deletion-Driven Prostate Cancer Mouse Models
	Activation of AKT/mTOR Signaling Pathway in SPOP Mutated Prostate Cancer
		SPOP Mutations Induce AKT/mTORC1 Activation via Elevation of Bromodomain and Extra-Terminal (BET) Family Proteins
		SPOP Mutant Mouse Models
	FOXO1 Dysregulation in Prostate Cancer
		FOXO1 and AR
		FOXO1 and ERG
		FOXO1 and RUNX2
	Cross Talk Between PI3K Signaling and Other Pathways in Prostate Cancer
		AKT Signaling and AR
		AKT Signaling and WNT/β-Catenin Signaling
		AKT Signaling and MAPK/ERK Signaling
	Targeting PI3K/AKT Signaling for Prostate Cancer Treatment
		PI3K/AKT Inhibitors Tested in Prostate Cancer
		A Limitation of Monotherapy with the PI3K Inhibitors
	Conclusions
	References
Androgen Receptor Dependence
	AR Structure and Function
	Androgen Regulation of AR Nuclear Translocation and DNA Binding
	AR Interactions with Chromatin
	AR Interactions with Co-regulators and Other Transcription Factors
	Therapeutic Targeting of the AR Signaling Axis
	AR Gene Amplification in CRPC
	AR Somatic Mutations in CRPC
	Amplification of an Upstream AR Enhancer in CRPC
	AR Variants in CRPC
	AR Cross-Talk with Other Signaling Pathways
	Therapeutic Advances in AR Targeting for CRPC-Stage Disease
	Emerging Therapeutic Strategies to Target AR in CRPC
	Conclusions
	References
Wnt/Beta-Catenin Signaling and Prostate Cancer Therapy Resistance
	Introduction to CRPCa and NEPCA
		Prostate Cancer Progression
		Mechanisms Driving CRPCa Progression
			AR-Dependent Mechanisms
			AR-Independent Mechanisms
		Neuroendocrine Differentiation of Carcinoma Cells
		The Cell of Origin of NEPCa
		Epigenetic Reprogramming Leads to NEPCa
		Conclusion
	Wnt/Beta-Catenin Signaling Pathway Overview
	Wnt/Beta-Catenin Signaling Is Involved in Prostate Carcinogenesis and Cancer Progression
		Wnt/β-Catenin Signaling and Cancer
		Wnt/β-Catenin Signaling in PCa
		Wnt/β-Catenin Signaling and PCa Metastasis
		Wnt/β-Catenin Signaling and Therapy Resistance
		Conclusion
	Wnt/Beta-Catenin Signaling Functionally Contributes to Prostate Cancer Progression
		Activation of Wnt/β-Catenin Signaling Bypasses PCa’s Dependency on AR Signaling
		Wnt/β-Catenin Signaling Induces NE Differentiation
		Wnt/β-Catenin Signaling and Epithelial to Mesenchymal Transition
		Wnt/β-Catenin Signaling and Cancer Stem Cells
	Mechanisms that Activate Wnt/Beta-Catenin Signaling in Prostate Cancer
		Activating Mutations of Wnt/β-Catenin Components in PCa
		Loss of Wnt/β-Catenin Signaling Inhibition
		Reactive Stroma Activates Wnt/β–­Catenin Signaling
		Androgen Deprivation Activates Wnt/β-Catenin Signaling
		Activation of Wnt/β-Catenin Signaling via Cross Talk with Other Signaling Pathways
		Loss of YAP/TAZ Expression Activates Wnt/β-Catenin Signaling
	Targeting Wnt/β-Catenin for the Treatment of CRPCA
	Conclusion
	References
Epigenetic Regulation of Chromatin in Prostate Cancer
	Introduction
	DNA Methylation as an Epigenetic Code for Prostate Tumor Development
	Histone Post-translational Modifications
	Histone Methylation in Prostate Cancer
		H3K4 Methylation
			H3K4 Methylation Writers
			H3K4 Methylation Erasers
			Epigenetic Therapies Targeting H3K4 Methylation
		H3K9 Methylation
			H3K9 Methylation Writers
			H3K9 Methylation Erasers
			Epigenetic Therapies Targeting H3K9 Methylation
		H3K27 Methylation
			H3K27 Methylation Writers
			H3K27 Methylation Erasers
			Epigenetic Therapies Targeting H3K27 Methylation
		H3K36 Methylation
			H3K36 Methylation Writers
			H3K36 Methylation Erasers
		H3K79 Methylation
			H3K79 Methylation Writer
			Epigenetic Therapies Targeting DOT1L
		Histone Lysine Methylation Readers
	Histone Acetylation in Prostate Cancer
		Acetylation Writers: HATs in Prostate Cancer
			Acetylation Erasers: HDACs in Prostate Cancer
			Acetylation Readers
			Epigenetic Therapies Targeting Histone Acetylation
	Chromatin Remodeling Complexes
	Conclusions and Outlook
	References
Oncogenic ETS Factors in Prostate Cancer
	Introduction
	ETS Family Transcription Factors
		What Is an ETS Factor?
		ETS Factors Aberrantly Expressed in Prostate Cancer
	ETS Gene Fusions in Prostate Cancer
		5′ Fusion Partners and Fusion Products
		Demographics of Patients with ETS-Positive Prostate Cancer
		Molecular Stratification of ETS-Positive Prostate Cancers
		Clinicopathological Value of Oncogenic ETS
		Generation of TMPRSS2/ERG Fusions
	ETS Factors as Oncogenes and Tumor Suppressors
		The Physiological Role of Oncogenic ETS
		Oncogenic ETS in Prostate Cancer Pathogenesis and Progression
		Recurrent ETS Fusions in Other Cancers
		Tumor Suppressive ETS Factors
	Molecular Mechanisms of Oncogenic Function
		DNA Binding
		Gene Regulation
		ETS/AP1
		GGAA Microsatellites
		Androgen Receptor
		Transcriptional Activation and Repression
		Oncogenic ETS and Chromatin
		Signaling Pathways and Oncogenic ETS
	Targeting Oncogenic ETS Factors
		ERG Targeting Peptide
			Small Molecule Inhibitors
		PARP1 Inhibitors
		ERG Targeting Vaccine
		Chemoresistance
		Degradation of ETS Factors
	Conclusion
	References
Neural Transcription Factors in Disease Progression
	Prostate Cancer Progression
		Prostate Cancer Cell Plasticity and Disease Progression
		Treatment-Induced Cell Plasticity: Emergent Phenotypes
	Transcription Factors
		Zinc Finger (ZF) Transcription Factors
		Helix-Loop-Helix (bHLH) Transcription Factors
		Homeodomain Transcription Factors
		HMG Domain Transcription Factors
		Forkhead Domain Transcription Factors
		Leucine Zipper (bZIP)
		Hetero-Domain Transcription Factors
	Inhibition of Neural Transcription to Attenuate Disease Progression
		REST
		HES and HEY Families of Transcription Factors
		KLFs
		TP53
	Conclusion
	References
Index