Therapeutic potential of Cell Cycle Kinases in Breast Cancer

Foreword
Preface
Acknowledgments
Contents
Editor and Contributors
1: Introduction to Breast Cancer
	1.1 Introduction
	1.2 History of Breast Cancer
	1.3 Surgery
	1.4 Radiation Therapy
	1.5 Systemic Therapy
	1.6 Hormone Therapy
	1.7 Chemotherapy
	1.8 Targeted Therapy
	1.9 Intrinsic Molecular Sub-Typing of Breast Cancer
		1.9.1 Luminal A and Luminal B Subtypes
		1.9.2 The HER2 Enriched Subtype
		1.9.3 The Basal-Like Subtype
		1.9.4 Triple-Negative Breast Cancer
	1.10 TNBC Sub-Typing and Clinical Implications
		1.10.1 Basal-Like Subtype
		1.10.2 Immunomodulatory (IM) Subtype
		1.10.3 Mesenchymal-Like Subtype
		1.10.4 Luminal Androgen Receptors (LAR) Subtype
	1.11 Brand-New Drugs
		1.11.1 Fulvestrant
		1.11.2 HER2 Blockers
	1.12 Conclusion
	1.13 Further Readings
	References
2: Current Treatment Approaches to Breast Cancer
	2.1 Introduction
	2.2 Breast Cancer Radiation Therapy
		2.2.1 External Beam Radiation Therapy
	2.3 Breast Brachytherapy
	2.4 Breast Cancer Chemotherapies
		2.4.1 Adjuvant Chemotherapy
		2.4.2 Neo-Adjuvant Chemotherapy
	2.5 Breast Cancer Endocrine Therapy
		2.5.1 Tamoxifen
		2.5.2 Aromatase Inhibitors
		2.5.3 Switching Trails in Endocrine Therapy
	2.6 Targeted Therapies in the Treatment of Breast Carcinoma
		2.6.1 HER2+ Malignant Tumor of Breast
		2.6.2 Trastuzumab
		2.6.3 Pertuzumab
		2.6.4 Conjugates of Antibodies and Drugs
		2.6.5 mTOR Pathways
		2.6.6 Receptor Tyrosine Kinase Inhibitors
	2.7 Function of Immunotherapies in the Diagnosis of Mammary Cancer
		2.7.1 Role of Checkpoint Inhibitors in Immunotherapy
		2.7.2 Breast Cancer Immunogenicity
	2.8 Surgical Treatment of Breast Cancer
		2.8.1 Breast-Conserving-Therapy (BCT)
		2.8.2 Mastectomy
		2.8.3 Dissection of the Axillary Lymph Nodes
		2.8.4 Sentinel Node Biopsy
	2.9 Summary
	2.10 Further Readings
	References
3: Introduction to Cell Cycle and Its Regulators
	3.1 Introduction
	3.2 Cell Cycle
		3.2.1 Interphase
		3.2.2 M Phase: The M Phase Is Classified into Two Phases
		3.2.3 Mitosis and Cytokinesis
	3.3 Time Determination for Cell Cycle
	3.4 G1 Is the Period of the Cell Cycle with the Most Variability
	3.5 Molecular Events During Cell Cycle
	3.6 Cell Cycle Regulation and Its Regulators
		3.6.1 Positive Regulators-Cyclins and CDKs
		3.6.2 Negative Regulators
	3.7 Degradation of Cyclins
	3.8 Checkpoints of the Cell Cycle
	3.9 Signaling Pathways in the Cell Cycle
	3.10 Importance of CDKs in Cell Cycle and Transcription
	3.11 The Significance of CDKs in the Cell Cycle
	3.12 CDKs and Transcription: What They Do
	3.13 Cancer, CDKs, and CDK Inhibitors
	3.14 Interphase CDKs Are Dysregulated in Tumor
	3.15 Summary
	3.16 Further Readings
	References
4: Cell Cycle and Cancer
	4.1 Introduction
	4.2 Cancer Development
	4.3 Cancer: Cell Cycle Dysregulation
	4.4 Cell Cycle
	4.5 Cell Cycle Entry and Progression
	4.6 Cell Cycle Checkpoints
	4.7 Regulation of Cyclin-CDK Complexes
	4.8 Activation by Phosphorylation
	4.9 CDK Inhibition by Phosphorylation
		4.9.1 CDK Inhibitors (CKI´s)
		4.9.2 CDK Interacting Protein/Kinase Inhibitory Protein (CIP/KIP)
		4.9.3 Inhibitors of Kinase (INK4)
	4.10 Role of M-C
	4.11 Role of APC/C Activators During Mitotic Division
	4.12 Spindle Assembly Checkpoint
	4.13 DNA Damage Checkpoints
	4.14 Therapeutic Agents
	4.15 Summary
	4.16 Further Readings
	References
5: Cell Cycle Dysregulation in Breast Cancer
	5.1 Introduction
	5.2 Oncogenic Factors of Cell Cycle
		5.2.1 Cyclin D
		5.2.2 Cyclin A
		5.2.3 Cyclin E
		5.2.4 Cyclin B
	5.3 Deregulation of CDKs in Breast Cancer
	5.4 Tumor Suppressive Proteins of the Cell Cycle
		5.4.1 p16
		5.4.2 p21
		5.4.3 p27
		5.4.4 p53
		5.4.5 Mutant p53
	5.5 Summary
	5.6 Further Readings
	References
6: Molecular Subtypes of Breast Cancer and CDk Dysregulation
	6.1 Introduction
	6.2 Genetic Expression
		6.2.1 Luminal A
		6.2.2 Luminal B
			6.2.2.1 Clinical Implications and Management
		6.2.3 HER-2 Enriched Subtype
			6.2.3.1 Clinical Implications and Management
		6.2.4 Triple-Negative or Basal-Like BC
			6.2.4.1 Genetic Expression
			6.2.4.2 Clinical Implications and Management
	6.3 Other Subtypes Under Investigation
	6.4 CDK Dysregulation in BC
	6.5 Role of CDK4/6 in Cell Cycle Control
		6.5.1 Palbociclib
		6.5.2 Ribociclib
		6.5.3 Abemaciclib
	6.6 Summary
	6.7 Further Readings
	References
7: Breast Tumor Microenvironment and CDKs
	7.1 Introduction
	7.2 The Tumor Microenvironment
		7.2.1 TME Components
		7.2.2 Composition
		7.2.3 Local Microenvironment
		7.2.4 Metastatic Microenvironment
	7.3 Breast Cancer Cell-Stromal Interactions
		7.3.1 Primary Site
		7.3.2 Tunneling Nanotubes
			7.3.2.1 Immune Cells
	7.4 T Regulatory Cell Infiltration in Tumor Microenvironment
	7.5 Cyclin-Dependent Kinases and Cell Cycle
	7.6 Cell Cycle, CDKs, and Cancer
	7.7 CDKS in BC Progression
	7.8 CDKs in Breast Cancer Metastasis
	7.9 Relative Numbers of Macrophages in Breast Cancer Progression
	7.10 Location of Macrophages in Breast Tumors
	7.11 Breast Cancer Cell Metastasis
	7.12 Breast Cancer Angiogenesis
	7.13 Conclusion
	7.14 Glossary and Abbreviations
		7.14.1 Glossary
	7.15 Further Readings
	References
8: CDK Dysregulation in Breast Cancer: A Bioinformatics Analysis
	8.1 Introduction
	8.2 Expression Profiles of CDKs in Molecular Subtypes of Breast Cancer
	8.3 Expression Analysis of CDKs in Breast Cancer
	8.4 CDK Expression and Various Clinicopathological Parameters
	8.5 Protein-Protein Interaction of CDKs in Breast Cancer
	8.6 Gene Ontology of CDKs
	8.7 Prognostic Significance of CDKs in Breast Cancer
	8.8 Role of CDKs in Breast Cancer
	8.9 Combination Therapy of CDK Inhibitors and PD1-PDL1 Antibodies
		8.9.1 Dinaciclib Enhances Anti-PD1 Mediated Tumor Suppression
		8.9.2 CDK4/6 Inhibitors Augment the Anti-Tumor Efficacy of PD1-PDL1 Immune Checkpoint Blockade
		8.9.3 Other Combination Therapies
	8.10 Summary
	8.11 Further Reading
	References
9: CDK1 Dysregulation in Breast Cancer
	9.1 Introduction
	9.2 Role of CDK1
	9.3 Dysregulation of CDK1 in BC
	9.4 The CDK1 and Breast Cancer
	9.5 Therapeutic Implications
	9.6 Undesirable Effects of Pan-CDK Inhibitors
	9.7 Summary
	9.8 Further Readings
	References
10: Cdk4/Cdk6 Dysregulation in Estrogen-Positive Receptor Breast Cancers
	10.1 Introduction
	10.2 Regulation of Cell Cycle by CDKs
	10.3 CDK4/6´s Dysregulation and Cell Cycle in BC
	10.4 CDK6/4and its Relation with the Breast Cancer
	10.5 CDK4/6 in Relation to ER+ Breast Cancer
	10.6 Endocrine Signaling, CDK4/CDK6 and Breast Cancer
	10.7 Role of CDKs in Transcription
	10.8 Targeting the CDK4/6:Cyc D Pathway Therapeutically
	10.9 Summary
	10.10 Further Readings
	References
11: Therapeutic Implications of CDKs in Breast Cancer
	11.1 Introduction
	11.2 Dysregulation of CDKs
	11.3 Functioning of CDK/Cyclins in the Cell Cycle
	11.4 Types of CDKs
	11.5 Role of CDKs in Breast Cancer
	11.6 Need for CDK Inhibitors for Use in BC Treatment
	11.7 Involvement of Other CDKs
	11.8 Types of CDK Inhibitors
	11.9 Pan-Inhibitors for BC Treatment
	11.10 Specific CDK Inhibitors for BC Treatment
	11.11 CDK4/6 Inhibitors and their Mechanism of Action
		11.11.1 Palbociclib
		11.11.2 Ribociclib
		11.11.3 Abemaciclib
		11.11.4 Other CDK Inhibitors
		11.11.5 Side Effects of CDK4/6 Inhibitors
	11.12 Summary
	11.13 Further Readings
	References
12: Novel CDK Inhibitors in Breast Cancer
	12.1 Introduction
	12.2 The Cyclin D-CDK4/6-Retinoblastoma Mechanism
	12.3 CDK Inhibitors and Breast Cancer
	12.4 Combinations of Novel CDK4/6 Inhibitors
		12.4.1 Inhibitors of PI3K/AKT/mTOR in Conjunction
		12.4.2 Combinations with Immune Checkpoint Inhibitors
	12.5 Potential Molecular Biomarkers of CDK4/6 Inhibition Responsiveness and Resistance
		12.5.1 RB Expression
		12.5.2 Alterations in Cyclin D1 or P16INK4A
		12.5.3 Mutational Profiles
		12.5.4 Other Gene Expression Profiles
	12.6 Summary
	12.7 Further Reading
	References
13: Targeting CDKs with Other Chemotherapeutic Drugs: A Combinatorial Approach
	13.1 An Introduction to Cell Cycle
	13.2 CDKs (Cyclin-Dependent Kinases)
	13.3 Pan-CDK Inhibitors
		13.3.1 Flavopiridol (Alvocidib)
		13.3.2 TGO2 (SB1317)
		13.3.3 P276-00
		13.3.4 Dinaciclib
		13.3.5 Seliciclib (Roscovitine/CYC202)
		13.3.6 Roniciclib
		13.3.7 PHA-793887
	13.4 Specific CDK Inhibitors
	13.5 CDK4/6 Inhibitors
		13.5.1 Palbociclib (PD-0332991)
		13.5.2 Abemaciclib
		13.5.3 Ribociclib (LEE O11)
	13.6 Specific CDK7 Inhibitors
	13.7 CDK9 Inhibitors
	13.8 CDK12 Inhibitors
	13.9 Natural Compounds Acting as CDK Inhibitors
	13.10 Summary
	13.11 Further Reading
	References
14: CDKs in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer
	14.1 Introduction
	14.2 CDKs and Cell Cycle Progression
	14.3 Dysregulation of CDKs in Breast Cancer
	14.4 CDKs as Therapeutic Targets of Breast Cancer
	14.5 CDK4/6 Inhibitors as a Monotherapeutic Approaches
		14.5.1 Palbociclib
		14.5.2 Ribociclib
		14.5.3 Abemaciclib
	14.6 CDK4/6 Inhibitors as a Combinational Approach
	14.7 Novel CDKIs
	14.8 Summary
	14.9 Further Readings
	References
15: CDk Inhibitor for Treatment of Breast Cancer
	15.1 Introduction
	15.2 The Cell Cycle and its Function
	15.3 Cell-Cycle Control and Cyclins
	15.4 Cyclin-Dependent Kinases: Role in Cell Cycle
	15.5 Proliferation of Breast Epithelial Cells and Cyclins
	15.6 Breast Cancer and Cyclins
	15.7 Role of Cyclins in Carcinogenesis of Mammary Glands
	15.8 In Breast Cancer; Cyclin Overexpression
	15.9 The CDK4/6 Targeted Preclinical Research
	15.10 CDK4/6Inhibitors´MechanismsofAction
	15.11 Prevention and Treatment
		15.11.1 Chemo-prevention
		15.11.2 Biological Prevention
	15.12 Summary
	15.13 Further Reading
	References
16: Response of Therapy in Cell-Cycle Regulatory Genes in Breast Cancer
	16.1 Introduction
	16.2 Treatment Response of the HER-2 Oncogene in Breast Cancer
	16.3 Endocrine Resistance
	16.4 Early Generation Cell Cycle/CDK Inhibitors and Microtubule Binding Drugs
		16.4.1 Inhibitors of TTK
		16.4.2 PLK4 Inhibitors
	16.5 Modulators for Downstream Signal Transduction
	16.6 Cell Cycle Modulators and Cyclins
	16.7 Summary
	16.8 Further Reading
	References
17: Different Cyclins and Their Significance in Breast Cancer
	17.1 Introduction
	17.2 History of Cell Cycle
	17.3 Cancer and Cell Cycle
		17.3.1 Cyclins
		17.3.2 Cyclins and Cell Cycle
	17.4 Different Types of Cyclins with Their Functional Significance:
		17.4.1 Cyclin D
		17.4.2 Cyclin E
		17.4.3 Cyclin A
		17.4.4 Cyclin B
		17.4.5 Cyclin H
		17.4.6 Cyclin T
		17.4.7 Cyclin K
		17.4.8 Cyclin F
		17.4.9 Cyclin G
	17.5 Role of Cyclins in Regulation of Transcription
	17.6 Role of Cyclins in Chromosomal Instability
	17.7 Summary
	17.8 Further Readings
	References