AGGRESSIVE BREAST CANCER -- AGGRESSIVE BREAST CANCER -- CONTENTS -- PREFACE -- RESEARCH AND REVIEW ARTICLES -- Chapter 1 THE HER2 ONCOGENE IN BREAST CANCER -- ABSTRACT -- INTRODUCTION -- HER PROTEIN RECEPTORS: SIGNAL TRANSDUCTION AND ONCOGENESIS -- Intracellular Signaling Pathways -- HER-Induced Cell Cycle Progression and Survival Pathways -- OVEREXPRESSION OF HER2 AND THE PROGNOSIS OF INVASIVE BREAST CANCER -- HER2 as A Prognostic Factor: Node-Positive Versus Node-Negative Disease -- HER Status and Lymphoid Infiltration -- HER2 and Progression of Early Breast Cancer Lesions to Invasive Carcinomas -- Relationship Between HER2 and Estrogen Receptor Expression -- HER2 ABNORMALITIES IN OTHER TYPES OF BREAST MALIGNANCIES -- HER2 OVEREXPRESSION IN MALE BREAST CARCINOMA -- Evaluating HER2 in Breast Tissue -- HER2 TARGETED THERAPY IN BREAST CANCER -- The Role of Trastuzumab in HER2 Overexpressing Breast Cancer -- The Role of Pertuzumab in HER2 Overexpressing Breast Cancer -- The Role of Trastuzumab-DM1 in HER2 Overexpressing Breast Cancer -- Inhibiting Several HER Receptors: The Role of Lapatinib in HER2 Overexpressing Breast Cancer -- Circulating Serum HER2 Levels -- PROPOSED RESISTANCE TO ANTI-HER2 THERAPIES -- Altered Receptor-Antibody Interaction -- Increased Signaling from other Receptors of the HER Family -- Increased Signaling from other Receptors Activating the MAPK and PI3K Pathways -- Constitutive Activation of Downstream Effectors -- HER2 OVEREXPRESSION AND CHEMOTHERAPY -- Anthracyclines -- Taxanes -- HER2 OVEREXPRESSION AND HORMONAL THERAPY -- CNS DISEASE IN HER2 OVEREXPRESSED BREAST CANCER -- CNS Metastases in Adjuvant Trials of Trastuzumab -- Prognosis of CNS Metastases in HER2 Overexpressing Breast Cancer -- CONCLUSION -- REFERENCES -- Chapter 2 MULTI-DRUG RESISTANCE AS A PROBLEM CHALLENGING BREAST CANCER CHEMOTHERAPY -- ABSTRACT.

INTRODUCTION -- 1) Non-Cellular MDR Mechanisms -- 2) Cellular MDR Mechanisms: -- 1. Changes in the intracellular accumulation and distribution of the drug -- 1a. Alteration of drug influx -- 1b. Alteration of drug efflux -- NORMAL TISSUE DISTRIBUTION -- PHYSIOLOGICAL FUNCTIONS OF P-GP -- PHARMACOLOGICAL FUNCTIONS OF P-GP -- P-GP SUBSTRATES -- 2. Increase in Drug Detoxification -- 3. Alterations of Drug Targets -- 4. Increase in DNA Repair Mechanism -- 5. Changes in Key Genes Controlling Cell Proliferation -- 5a. Changes in genes responsible for cell cycle control -- 5b. Abrogation of apoptosis -- 6. Micro-Environmental Stress-Mediated Resistance of Solid Tumors -- 7. Cancer Cell Dormancy and Resistant Cancer Stem Cells -- MODULATION OF MDR PHENOTYPE -- I. Circumvention of Drug Resistance Induced by P-Gp Pump Protein -- A. Chemo-sensitization by P-gp inhibitors -- B. Chemical modification or the use of anti-cancer pro-drug strategy -- C. Targeting P-gp pump protein -- II. MDR Circumvention by Steroidal Agents -- III. Incorporation of Alternative Novel Anti-Tumor Agents -- IV. Molecular Targeting of MDR Signaling Pathways & Gene Therapy Approaches -- A. MDR-1 transcriptional regulators -- B. Targeting apoptosis signaling pathways -- C. Targeting proteasome for reversal of stress-mediated resistance of solid tumors -- D. Targeting angiogenic and proliferative markers of cancer drug resistance -- V. Nanotechnology for Overcoming Mdr -- VI. Stem Cell Research for Modulation of MDR -- VII. Pharmacogenomics and Screening for Molecular Signatures of MDR -- CONCLUSION -- ACKNOWLEDGEMENT -- REFERENCES -- Chapter 3 SIGNAL TRANSDUCTION AND METASTASIS SUPPRESSION: THE ROLE OF RAF KINASE INHIBITOR PROTEIN (RKIP) IN BREAST CANCER -- ABSTRACT -- INTRODUCTION -- THE RKIP GENE AND PROTEIN -- THE LOCATION OF RKIP -- RKIP IN SIGNALING.

1. The Raf-MEK-MAPK Signaling Pathway -- 2. The G Protein-Coupled Receptor (GPCR) Signaling Pathway -- 3. The NK-Κb Signaling Pathway -- RKIP FUNCTION IN CANCER -- 1. RKIP in Cell Division and Genomic Stability -- 2. RKIP in Cell Apoptosis -- 3. RKIP and Cell Migration -- 4. RKIP in Cancer Metastasis -- RKIP SUPPRESSES BREAST CANCER METASTASIS -- CONCLUSION -- REFERENCES -- Chapter 4 BRCA1-ASSOCIATED PROTEINS: NOVEL TARGETS FOR BREAST CANCER RADIATION THERAPY -- ABSTRACT -- INTRODUCTION -- RADIATION THERAPY FOR BREAST CANCER -- BRCA1 IN RESISTANCE TO BREAST CANCER RADIATION THERAPY -- ROLE OF BRCA1 AND ASSOCIATED PROTEINS IN BREAST CANCER ETIOLOGY -- BRCA1-Associated Proteins: Functional Modifiers of BRCA1 Activity -- BRCA1-Associated Proteins as Potential Targets of Breast Cancer Therapies -- SUMMARY -- ACKNOWLEDGMENT -- REFERENCES -- Chapter 5 PERIPHERAL BENZODIAZEPINE RECEPTOR AS A BIOMARKER FOR BREAST CANCER -- ABSTRACT -- INCIDENCE OF BREAST CANCER -- WHAT IS PBR? -- ROLE OF PBR IN CANCER -- IMPACT OF DIET ON PBR MEDIATED CANCER -- THERAPEUTIC APPROACH TO PREVENT BY TARGETING PBR -- ACKNOWLEDGMENT -- REFERENCES -- Chapter 6 PHOSPHOLIPIDS AS BIOMARKERS FOR BREAST CANCER -- ABSTRACT -- INTRODUCTION -- Phospholipid Biosynthesis Pathway -- Function of Phospholipids in the Cell -- Altered Membrane Choline Phospholipid Metabolism of Human Mammary Epithelial Cells -- Altered Membrane Choline Phospholipid Metabolism in Breast Cancer Animal Models -- CONCLUSION -- ACKNOWLEDGMENT -- REFERENCES -- Chapter 7 GENETICALLY ENGINEERED T-CELLS FOR ADOPTIVE IMMUNOTHERAPY OF BREAST CANCER -- ABSTRACT -- INTRODUCTION -- GENERATION OF HUMAN T LYMPHOCYTES ARMED WITH AN HER2/NEU -SPECIFIC TRIPARTITE CHIMERIC RECEPTOR -- Therapeutic Potential of T-Bodies in Murine Models -- CONCLUSION -- ACKNOWLEDGMENTS -- REFERENCES -- Chapter 8 TRASTUZUMAB RESISTANCE.

ABSTRACT -- INTRODUCTION -- MECHANISMS OF RESISTANCE -- 1). Inability of the Antibody to Bind to its Target -- 2). Activation of other HER Family Receptors -- 3). Increased Signaling of IGF-1R -- 4). Dysregulation of Downsteam Signaling -- CONCLUSION -- REFERENCES -- Chapter 9 LYMPHATIC SPREADING PROPENSITY AND ABERRANT MUC1 BEARING TN/TN-LIKE CARBOHYDRATE OF AGGRESSIVE BREAST CANCER CELLS -- ABSTRACT -- INTRODUCTION -- I. EXPRESSION OF VICIA VILLOSA AGGLUTININ (VVA)-BINDING CARBOHYDRATE OF BREAST CANCER CELLS IN RELATION TO THE LYMPHATIC SPREAD -- I-1. Materials and Methods for Carbohydrate Network Analysis -- I-2. Frequency of Positive Staining of all the Cases and Changes by T Factor and Histological Subtype -- I-3. Relationship between Lymph Node Metastasis and Reactivity with Lectin or Monoclonal Antibodies -- I-4. Carbohydrate Network Associated with Lymph Node Metastasis -- I-5. Correlation Between Lymphatic Vessel Invasion or Vein Invasion and Carbohydrate Expression of Cancer Cells -- I-6. Significance of Combination Analysis of Carbohydrate Antigen Expression on Lymph Node Metastasis Status of Primary Breast Cancer Cells -- II. VVA-BINDING CARBOHYDRATE(S) ASSOCIATED WITH AGGRESSIVE GROWTH OF BREAST CANCERS: PARTIAL MOLECULAR CHARACTERIZATION AND IDENTIFICATION -- II-1. Localization of Carbohydrate Antigen by Staining With VVA and HB-Tn1 Mab in Primary Breast Cancer -- II-2. Correlation of Breast Cancer Aggressiveness with Expression of VVA-Binding Protein, HB-Tn1-Binding Protein, and MUC1 -- II-3. Partial Characterization of VVA-Binding Carbohydrates in Relation to Tn Antigen -- II-4. MUC1 as a Possible Carrier Protein of VVA-Binding Carbohydrate(S) and HB-Tn1-Reactive Tn Antigen -- (1) Relationship between MUC1 expression of breast cancer cells and clinicopathological parameters.

(2) Demonstration of small-sized atypical MUC1 and breast cancer aggressiveness -- III. ABERRANT MUC1 BEARING TN/TN-LIKE ANTIGEN IN RAT ASCITES HEPATOMA CELLS WITH STRONG LYMPH NODE METASTASIS PROPENSITY -- CONCLUSION -- ACKNOWLEDGMENT -- REFERENCES -- EXPERT COMMENTARY -- Commentary RELATIONSHIP BETWEEN CARBOHYDRATE EXPRESSION PROFILES OF CANCER CELLS AND PROGNOSIS OF BREAST CANCER PATIENTS -- INTRODUCTION -- REFERENCES -- INDEX -- Blank Page.