Molecular Basis of Breast Cancer, Softcover reprint of the original 1st ed. 2004
Prevention and Treatment

1 Epidemiological Considerations in Breast Cancer.- 1.1 Introduction.- 1.2 Geographical Influences.- 1.3 Radiation as an Etiologic Agent.- 1.4 Electromagnetic Fields.- 1.5 Environmental Pollutants.- 1.6 Reproductive Factors.- 1.7 Environmental Exposures at a Young Age that Increase the Risk of Breast Cancer.- 1.7.1 Endocrinological Milieu.- 1.7.2 Smoking.- 1.7.3 Alcohol as a Neuroendocrine Disruptor.- 1.7.4 Effect of Light on Puberty and Breast Cancer Risk.- 1.8 Conclusions.- References.- 2 The Breast as a Developing Organ.- 2.1 Introduction.- 2.2 Prenatal and Perinatal Development.- 2.3 Postnatal Development.- 2.4 Pregnancy.- 2.5 Postlactational Changes.- 2.6 The Menopausal Breast.- 2.7 Parenchyma-Stroma Relationship.- 2.8 Genetic Influences in Breast Development.- 2.9 Cell Proliferation and Hormone Receptors in Relation to Breast Structure.- 2.10 Extracellular Matrix Protein Expression in the Normal Breast.- 2.10.1 Angiogenic Index in the Lobular Structures.- 2.10.2 Elastininthe Lobular Structures.- 2.10.3 Tenascin in the Lobular Structures.- 2.11 Genomic Profile of Lobular Structures in Nulliparous and Parous Women’s Breasts.- 2.12 Novel Differentiation-Associated Serpin is Upregulated During Lobular Development.- 2.13 Mammary-Derived Growth Inhibitor.- 2.14 Conclusions.- References.- 3 Endocrine Control of Breast Development.- 3.1 Introduction.- 3.2 Steroid Receptors, Cell Proliferation, and Breast Differentiation.- 3.2.1 Relationship of Proliferating and ERa-Positive Cells in the Human Breast.- 3.2.2 Cell Proliferation, ERct, and PgR Content in the Rat Mammary Gland.- 3.2.3 Biological Significance.- 3.3 Human Chorionic Gonadotropin as a Differentiating Agent in the Human Breast and in the Rodent Mammary Gland.- 3.3.1 Evidence for a Receptor for Human Chorionic Gonadotropin in Human Breast Epithelial Cells.- 3.3.2 Human Chorionic Gonadotropin Receptor in the Rat Mammary Gland.- 3.3.3 Biological Significance of the LH/hCG Receptor.- 3.4 Effect of Human Chorionic Gonadotropin on Human Breast Epithelial Cells.- 3.4.1 Effect on Protein Synthesis and In Vitro Translational Products of mRNA.- 3.4.2 Effect of Human Chorionic Gonadotropin Treatment on Inhibin Synthesis.- 3.4.3 Effect of Hormones on the Proliferative Activity of Cultured Normal and Neoplastic Human Breast Epithelial Cells.- 3.4.4 Biological Significance of the hCG-Inhibin Pathway.- 3.5 Homeobox Genes’ Expression and Their Modulation by Human Chorionic Gonadotropin in Human Breast Epithelial Cells.- 3.5.1 Class I Homeobox Gene Expression in Human Breast Epithelial Cell Lines.- 3.5.2 Human Chorionic Gonadotropin Modulates Expression of Homeobox Genes.- 3.5.3 Human Chorionic Gonadotropin and HOXA2 Inhibit AP-1.- 3.6 Human Chorionic Gonadotropin and Histone Acetylation.- 3.7 Conclusions.- References.- 4 The Role of Estrogen in Breast Cancer.- 4.1 Introduction.- 4.2 Sources of Estrogens in Human Breast Tissue.- 4.3 Role of Estrogens in Human Breast Proliferation.- 4.4 Estrogens in Human Breast Carcinogenesis.- 4.4.1 Receptor-Mediated Pathway.- 4.4.2 Oxidative Metabolism of Estrogen.- 4.4.2.1 Estrogen as Mutagenic Agents.- 4.4.2.2 The Mechanism by Which Estrogens Induce Mutations.- 4.4.2.3 Additional Factors Contributing to the Carcinogenic Effect of Estrogen.- 4.4.3 Estrogens as Inducers of Aneuploidy.- 4.5 Biological Demonstration That Estrogens Are Carcinogenic in the Human Breast.- 4.5.1 The Proof of Principle.- 4.5.2 The In Vitro Model of Cell Transformation.- 4.5.2.1 Transformation Effect of Estrogen in MCF-10F Cells.- 4.5.2.2 Transformation Effect of the Estrogen Metabolites.- 4.5.2.3 Role of Antiestrogens in the Expression of the Transformation Phenotype.- 4.5.2.4 Detection of Estrogen Receptors in MCF 10F-Cells.- 4.5.2.5 Evidence for a Role of ER? and Metabolic Activation of Estrogen in the Transformation of Human Breast Epithelial Cells.- 4.5.3 Genomic Changes Induced by Estrogen and Its Metabolites in Human Breast Epithelial Cells.- 4.5.4 Other Genomic Changes Induced by Estrogen and Its Metabolites in the Transformation of Human Breast Epithelial Cells.- 4.5.5 Chromosomal Alterations Induced by Estrogen and Its Metabolites.- 4.6 A Unified Concept in the Role of Estrogen in Breast Cancer.- References.- 5 Pathogenesis of Breast Cancer.- 5.1 Introduction.- 5.2 The Site of Origin of Breast Cancer.- 5.3 Supporting Evidence for the Site of Origin of Breast Cancer.- 5.3.1 In Vitro Studies.- 5.3.2 Breast Architecture as a Determining Factor in the Susceptibility of the Human Breast to Cancer.- 5.3.3 Specific Considerations on the Relation Between Lobular Development and Familial Breast Cancer-Related Genes.- 5.3.4 Unifying Concepts.- 5.4 Molecular Changes in the Initiation and Progression of Breast Cancer.- 5.4.1 Differential Expression of Human Ferritin H Chain Gene and Breast Cancer.- 5.4.2 S100P Calcium-Binding Protein as a Marker of Cancer Initiation.- 5.4.3 Role of Intracellular Ca2+ During Cell Immortalization and Cell Transformation.- 5.4.4 The Role of Ca Intracellular and S100 Protein Expression in the Formation of Microcal-cifications in Preneoplastic and Neoplastic Lesions of the Breast.- 5.5 Genetic Changes Associated with Initiation and Progression of Breast Cancer.- 5.5.1 Laser Capture Microdissection.- 5.5.2 Microsatellite Instability and Loss of Heterozygosity in Microdissected Lesions of the Breast.- 5.5.3 Example of Breast Cancer Genetic Heterogeneity Revealed by Laser Capture Microdissection Technique.- 5.6 Summary and Conclusions.- References.- 6 Animal Models for Human Breast Cancer.- 6.1 Introduction.- 6.2 General Concepts.- 6.3 Chemically-Induced Mammary Tumorigenesis.- 6.4 Radiation-Induced Mammary Tumorigenesis.- 6.5 Genetic Background and Mammary Carcinogenesis.- 6.6 Pathogenesis of Rat Mammary Tumors.- 6.7 Mammary Gland Differentiation as a Modulator of Carcinogenic Response.- 6.7.1 Cell of Origin of Rat Mammary Carcinomas.- 6.7.2 Cell Kinetics and Mammary Carcinogenesis.- 6.7.3 Role of the Stroma in the Pathogenesis of Mammary Cancer.- 6.8 Pathological Classification of Rat Mammary Tumors.- 6.8.1 Epithelial Neoplasms.- 6.8.1.1 Intraductal Papilloma.- 6.8.1.2 Papillary Cystadenoma.- 6.8.1.3 Adenoma.- 6.8.1.4 Precancerous Lesions: Intraductal Proliferation.- 6.8.1.5 Carcinoma In Situ.- 6.8.1.6 Invasive Ductal Carcinomas.- 6.8.2 Stromal Neoplasms.- 6.8.2.1 Fibroma.- 6.8.2.2 Fibrosarcoma.- 6.8.3 Epithelial-Stromal Neoplasms.- 6.8.3.1 Fibroadenoma.- 6.8.3.2 Carcinosarcoma.- 6.8.4 Nonneoplastic Lesions.- 6.9 Differential Diagnosis of Mammary Tumors.- 6.9.1 Macroscopic Criteria.- 6.9.2 Histopathological Criteria.- 6.9.3 Biological Criteria.- 6.10 Biological Importance of the Chemical Carcinogen-Induced Rat Mammary Tumor Model.- 6.11 Genetically Engineered Mice Model.- 6.11.1 Anatomy of the Mouse Mammary Gland.- 6.11.2 Classification of Genetically Engineered Mouse Mammary Lesions.- 6.11.2 Comparative Pathology of the Model Systems.- References.- 7 In Vitro Models for Human Breast Cancer.- 7.1 Introduction.- 7.2 Growth Properties of Normal Human Breast Epithelial Cells In Vitro.- 7.3 The MCF-7 Cell as a Model of Human Breast Cancer In Vitro.- 7.3.1 Morphological and Growth Characteristics of MCF-7 Cells.- 7.3.2 Growth of MCF-7 Cells in Tridimensional Matrix.- 7.3.3 Growth of MCF-7 Cells in Athymic Mice.- 7.4 Growth Properties of Immortal Human Breast Epithelial Cells In Vitro.- 7.4.1 Telomerase Activation.- 7.4.2 Abrogation of Cell Cycle Control.- 7.4.3 Genes Preferentially Expressed During Cell Immortalization.- 7.5 Transformation of Primary Cultures of Human Breast Epithelial Cells with Chemical Carcinogens.- 7.6 In Vitro System of Cell Transformation.- 7.6.1 Transformation of Human Breast Epithelial Cells with c-Ha-ras Oncogene.- 7.6.2 Transformation of Human Breast Epithelial Cells with Chemical Carcinogens.- 7.6.3 Ha-ras Enhances the Transformation of Human Breast Epithelial Cells with Chemical Carcinogens.- References.- 8 Genomic Basis of Breast Cancer.- 8.1 Introduction.- 8.2 Genomic Changes Observed in Breast Cancer.- 8.3 Microsatellite Instability as an Early Genomic Event in Breast Cancer Initiation.- 8.4 Other Genomic Changes Associated with Immortalization, Transformation, and Tumorigenesis.- 8.4.1 Tumor Suppressor Gene p53.- 8.4.2 Oncogenes.- 8.4.2.1 c-Ha-ras.- 8.4.2.2 c-neu, int-2, and c-myc Oncogenes.- 8.4.3 mdm2 Gene.- 8.4.4 Loss of Heterozygosity and Fluorescence In Situ Hybridization Analysis of Chromosome 17p.- 8.5 Search for Specific Functional Relevance of the Genomic Changes.- 8.5.1 Reversion of the Immortalization Phenotype.- 8.5.2 Reversion of the Transformation but Not Immortalization Phenotype.- 8.6 The Role of Mismatch Repair in the Initial Event of Carcinogenesis.- 8.7 Unifying Concepts.- References.- 9 Preventive Strategies in Breast Cancer.- 9.1 Introduction.- 9.2 Physicoprevention with Prophylactic Mastectomy.- 9.3 Bioprevention of Hereditary Breast Cancer.- 9.4 Chemoprevention Against Acquired Somatic Mutations.- 9.4.1 Limiting Accumulation of Chemical Carcinogens.- 9.4.2 Enhancing Excretion of Xenobiotics.- 9.4.2.1 Organosulfur Compounds.- 9.4.2.2 Indole-3-Carbinol.- 9.4.2.3 Phytoalexin.- 9.4.2.4 Triterpenoids.- 9.4.3 Eliminating Oxidative Stress.- 9.4.3.1 Carotenoids.- 9.4.3.2 Vitamin E and Selenium.- 9.4.3.3 Tea and Polyphenolic Antioxidants.- 9.4.3.4 Flavonoids.- 9.5 Chemoprevention Against Epigenetic Alterations.- 9.5.1Restricting Fat Caloric Consumption.- 9.5.2Maintaining Proper Endocrine Milieu.- 9.5.2.1 Steroids.- 9.5.2.2 Aromatase Inhibitors.- 9.5.2.3 Estrone Sulfatase Inhibitors.- 9.5.2.4 Dehydroepiandrosterone.- 9.5.2.5 Genistein.- 9.6 Melatonin.- 9.7 Eicosanoids.- 9.8 Estrogen Antagonists.- 9.8.1 Antiestrogens.- 9.8.2 Aryl Hydrocarbon Receptor Agonists.- 9.9 Interrupting Carcinogenic Signal Transduction.- 9.9.1 Inhibitors of Receptor Tyrosine Kinases.- 9.9.2 Inhibitors of p21ras Farnesylation.- 9.9.3 Inhibitors of HMG-CoA Reductase.- 9.9.4 Monoterpenes.- 9.9.5 Eicosapentaenoic Acid.- 9.10 Inducing Breast Cell Differentiation.- 9.10.1 Retinoids.- 9.10.2 Pregnancy and Human Chorionic Gonadotropin.- 9.11 N-Chemoprevention Against Growth of Neoplasms: Suppressing the Growth of Neoplastic Cells.- 9.11.1 Vitamin D and Calcium.- 9.11.2 Ornithine Decarboxylase Inhibitors.- 9.12 O-Inhibiting Neovascularization or Angiogenesis.- 9.13 Socioprevention of Breast Cancer.- 9.14 Summary and Future Perspectives.- References.- 10 The New Paradigm in Breast Cancer Prevention.- 10.1 Rationale for a New Paradigm.- 10.2 The New Paradigm.- 10.3 Epidemiological and Clinical Basis for the New Paradigm.- 10.4 Data from Experimental Animal Studies.- 10.4.1 Pregnancy.- 10.4.2 Placental Hormones.- 10.4.3 Estrogenic and Progestagenic Agents.- 10.4.4 Role of Pregnancy and Chorionic Gonadotropin in Mammary Gland Differentiation and Cancer Initiation.- 10.5 Role of Human Chorionic Gonadotropin in Breast Cancer Progression.- 10.5.1 Mammary Gland Development Under Influence of Human Chorionic Gonadotropin.- 10.5.2 Hormonal Profile Induced by Human Chorionic Gonadotropin.- 10.5.3 Effect of Human Chorionic Gonadotropin on Terminal End Buds, Intraductal Proliferations, and Ductal Carcinomas In Situ.- 10.5.4 Effect of Human Chorionic Gonadotropin Treatment on DMBA-Induced Tumor Progression.- 10.6 Effect of Human Chorionic Gonadotropin on Inhibin Expression and Its Relation with the Activation of Early Response Genes.- 10.7 Effect of Human Chorionic Gonadotropin on Programmed Cell Death Gene Expression.- 10.7.1 Effect of Human Chorionic Gonadotropin in the Mammary Gland of Animals Treated with DMBA.- 10.7.2 Effect of Human Chorionic Gonadotropin Treatment on the Expression of Apoptotic Genes in DMBA-Induced Mammary Carcinomas.- 10.7.3 Effect of Human Chorionic Gonadotropin Treatment on the Expression of Apoptotic Genes in the Ovary.- 10.7.4 Effect of Human Chorionic Gonadotropin Treatment on Apoptosis.- 10.8 Evidence of a Direct Effect of Human Chorionic Gonadotropin in Mammary Epithelial Cells.- 10.8.1 Human Chorionic Gonadotropin Has an Inhibitory Effect on DMBA Mammary Carcinogenesis in Ovariectomized Animals.- 10.8.2 Effect of Human Chorionic Gonadotropin in Human Breast Epithelial Cells In Vitro.- 10.9 Tumoristatic Effect of Human Chorionic Gonadotropin on Malignant Human Breast Epithelial Cells Transplanted in Heterologous Host.- 10.10 Effect of Recombinant Human Chorionic Gonadotropin on Primary Breast Cancer.- 10.11 Isolation and Characterization of New Genes Induced by Human Chorionic Gonadotropin.- 10.11.1 Genes Induced by Human Chorionic Gonadotropin in Human Breast Epithelial Cells In Vitro.- 10.11.2 Genes Induced by Human Chorionic Gonadotropin in the Rat Mammary Gland.- 10.11.2.1Morphological Phenotypes Induced by Urinary and Recombinant Human Chorionic Gonadotropin.- 10.11.2.2 Differential Display and Northern Blot Analysis.- 10.12 Genomic Signature Induced by Human Chorionic Gonadotropin and Pregnancy.- 10.13 Unifying Concepts.- References.