Contents 1 The Windows of Susceptibility to Breast Cancer 2 The So Called Pre-Neoplastic Lesions and Carcinoma In Situ

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1 Contents 1 The Windows of Susceptibility to Breast Cancer Introduction Risk Factor and Etiological Agents The Concept of the Windows of Susceptibility to Carcinogenesis The Windows of Susceptibility Apply to Human Breast Cancer Effect of Hormones on Breast Cancer Hormones as Carcinogens Role of Breast Development and Cancer Fertility and Breast Cancer Risk Conclusions References The So Called Pre-Neoplastic Lesions and Carcinoma In Situ Introduction The So Called Pre-neoplastic Lesions Ductal Hyperplasia Lobular Hyperplasia Atypical Ductal and Lobular Hyperplasia The Histopathology of DCIS Comedocarcinoma Papillary Carcinoma in Situ Solid Form of DCIS Cribriform Carcinoma In Situ Micropapillary Carcinoma In Situ Other Forms of DCIS Lobular Carcinoma In Situ (lcls) Differential Diagnosis References v

2 vi Contents 3 The Pathobiology of the Breast Cancer Invasive Process Introduction Epithelial Mesenchymal Transition (EMT) A Human Breast Cancer Cell Model of EMT Other Factors Involved in the EMT Conclusions References The Invasive Breast Cancer Types Introduction The Invasive Cancer Subtypes Invasive Ductal Carcinoma No Otherwise Specified (NOS) Invasive Cribriform Carcinoma Mucinous Carcinoma Tubular Carcinoma Medullary Carcinoma Invasive Papillary Carcinoma Apocrine Carcinoma Juvenile (Secretory) Carcinoma Carcinomas with Neuroendocrine Features Metaplastic Carcinoma Inflammatory Carcinoma Paget s Disease Invasive Lobular Carcinoma Mixed Ductal and Lobular Carcinoma Microinvasive Breast Carcinoma References The Molecular Basis of Breast Cancer Subtypes Introduction Initial Genomic Classification Extended Classifications: Molecular Subtypes The Molecular Taxonomic Breast Cancer International Consortium (METABRIC) Classification Genomic Classification Based on the Normal Cell Subtype References Stem Cells in Breast Cancer Introduction Cell Markers for Identifying the Stem Cell in the Mammary Gland Estrogen Receptor as a Marker of Stem Cells in the Mammary Gland MCF10F Cells Behave as a Stem Cell In Vitro The MCF-10F in Estrogen Induced Carcinogenesis

3 Contents vii 6.6 The Evidence for the Role of Stem Cells in the Pregnancy Preventive Effect During Carcinogenesis Isolation of the Stem Cells from the Rat Mammary Gland Role of the Mammary Gland Stem Cell in the Prevention of Breast Cancer References The Mechanisms of Breast Cancer Metastasis Introduction Route of Metastasis The Mechanism of Metastasis The Lymphatic Vessels as a Path for Metastatic Dissemination The Concept of Stem Cells and Metastasis Role of Circulating Tumor Cells in Breast Cancer Metastasis Metastasis of Breast Cancer to Specific Sites Role of P53 and Metastasis Problems with the Treatment of Metastasis References How to Build Up Adequate Prognostic Markers in the Molecular Biology Context of Breast Cancer Introduction Tumor Grading Tumor Grading and Prognosis of Breast Cancer Characteristics of the Primary Tumor, Such as ER Status, Tumor Size, and Histologic Grade, and Lymph Node Status at the Time of Surgery Served Significantly to Predict the Outcome of the Disease with Regard to Both Recurrence and Patient Survival ER and PR as Biomarkers of Prognosis Role of HER2 in Breast Cancer Diagnosis and Treatment Evaluation of KI Molecular Profiling of Breast Cancer General Considerations References Preclincial Models for Studying Breast Cancer Introduction Xenotransplantation Xenografts for Testing the Tumorigenicity of Chemically Transformed Cells The Oncogene C-HA-RAS Induces a Tumorigenic Phenotype in Human Breast Epithelial Cells Tumorigenicity of 17-β Estradiol Transformed Human Breast Epithelial Cells

4 viii Contents 9.3 The Labeling of Cancer Cells for an In Vivo Imaging System A Model for Triple Negative Breast Cancer Development of XtMCF and LmMCF Cell Lines Molecular Characterization of XtMCF and LmMCF Cells XtMCF and LmMCF Cells Are Differed from bsmcf- luc Cells in Migration, Solid Masses Formation, and Colony Formation Capacity XtMCF and LmMCF Cells Are Highly Tumorigenic and Metastatic In Vivo Classification of Xenografts and Lung Metastases Formed by XtMCF and LmMCF Cells XtMCF and LmMCF Cells Present CD24 weak + + /CD44 /EpCAM Cancer Stem Cells Properties, EGF-Like Domain of EpCAM Is Cleaved Off Relevance of the Triple Negative Breast Cancer Model References Biological Basis of Breast Cancer Prevention Introduction Pregnancy as a Physiological Process That Prevent Breast Cancer Breast Development and Differentiation as the Biological Clue in Cancer Prevention Basis of the Dual Effect of Late Pregnancy in the Increase Risk of Breast Cancer Current Strategies in Breast Cancer Prevention Experimental Data Supporting the New Strategy in Prevention Clinical Studies Supporting the New Strategy in Prevention Pregnancy and HCG Induce Permanent Genomic Imprinting or a Specific Signature of Protection Developing a Prevention Clinical Trial Using HCG Summary and Conclusions References

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