ErbB2/Neu overexpression is observed in 20--30% of human mammary carcinomas and correlates with poor prognosis. We have demonstrated that four ErbB2/Neu tyrosine autophosphorylation sites (YB, YC, YD and YE) are sufficient to mediate transforming signals in vitro and bind distinct adapter proteins, suggesting that transformation functions through distinct pathways. To study the role of each individual tyrosine autophosphorylation site in mammary tumourigenesis, we derived transgenic mice expressing mutant ErbB2/Neu receptors in the mammary gland. Recently, we showed that YB and YD female transgenic mice developed mammary tumours with differences in tumour latency, morphology, and metastatic potential. To further understand the role of the autophosphorylation sites, I characterized the YC and YE transgenic mouse models and showed that although, they exhibit similar phenotypes, they also differ in their latency, morphology and metastatic rate compared to the YB and YD transgenic mouse models. This suggests that recruitment of specific adaptor proteins has distinct biological effects on ErbB2/Neu-mediated mammary tumourigenesis.

Thesis (M.S.)--University of Wisconsin-Madison, 1994. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 31-35).

Thesis (Ph.D.)--University of Alabama at Birmingham, 2007. / Title from PDF title page (viewed on Sept. 16, 2009). Includes bibliographical references (p. 87-96).

Thesis (doctoral)--Nijmegen, 1982.

No description available.

Breast cancer is a heterogeneous disease comprised of distinct biological entities that correlate with diverse clinical outcomes. Gene expression profiling has divided this heterogeneity into luminal, ERBB2+ and basal molecular subtypes. Basal breast cancers are difficult to treat as they lack expression of candidates suitable for targeted therapies and are associated with poor outcome. / Elevated protein level of the hepatocyte growth factor receptor, MET, is observed in 20% of human breast cancers and correlates with poor prognosis. However, the role of MET in mammary tumorigenesis is poorly understood. To address this, we generated a murine model that expresses weakly oncogenic mutants of Met (Metmt) in the mammary epithelium under the transcriptional control of the mouse mammary tumor virus promoter. We demonstrate that Metmt induces mammary carcinomas with diverse phenotypes and used gene expression microarrays to elucidate gene expression changes induced by Met. Since mammary tumors contained variable contents of epithelium and stroma, we used laser capture microdissection to procure epithelial cells for microarray analysis. Based on immunohistochemistry and expression profiling, we show that Metmt produces tumors with luminal or basal characteristics. From hierarchical clustering, Metmt-induced basal tumors clustered with murine models that share features of epithelial to mesenchymal transition and human basal breast cancers. Moreover, Metmt basal tumors clustered with human basal breast cancer. The status of MET among the human breast cancer subtypes has not previously been addressed. We demonstrate that MET levels are variable across molecular subtypes but show elevation in the basal subtype and correlates with poor outcome. We used a candidate gene approach derived from microarray data to gain an understanding of signals required for Met-dependent tumorigenesis. We investigated Nck adaptor proteins and demonstrate a role for Nck in cell motility and actin dynamics of Met-dependent breast carcinoma cells and show elevated expression in human basal breast cancers. By generating a unique mouse model in which Met is expressed in mammary epithelia, with the examination of MET levels in human breast cancer, we have established a novel link between MET and basal breast cancer. This work identifies poor outcome basal breast cancers that may benefit from anti-MET therapies.

No description available.

Lai Kin Ming Connie. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 121-141). / Abstracts in English and Chinese. / Chapter Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Introduction on growth cycle of mushroom --- p.1 / Chapter 1.2 --- Literature review of mushroom biological activities --- p.3 / Chapter 1.2.1 --- Various bioactivities of mushroom --- p.3 / Chapter 1.2.2 --- Components responsible for various bioactivities of mushrooms --- p.3 / Chapter 1.3 --- Mushroom polysaccharides and polysaccharide-protein complexes --- p.5 / Chapter 1.3.1 --- Polysaccharides important for antitumor effects --- p.5 / Chapter 1.3.2 --- Polysaccharide-protein complexes important for antitumor effects --- p.7 / Chapter 1.4 --- Structure-function relationship of antitumor activities of polysaccharides --- p.8 / Chapter 1.4.1 --- Effect of molecular mass --- p.8 / Chapter 1.4.2 --- Effect of linkages --- p.9 / Chapter 1.4.3 --- Effect of degree of branching --- p.9 / Chapter 1.4.4 --- Effect of conformation --- p.10 / Chapter 1.5 --- Immunomodulatory effects of mushroom polysaccharides and polysaccharide-protein complexes --- p.11 / Chapter 1.5.1 --- Immunomodulatory effects of polysaccharides --- p.11 / Chapter 1.5.1.1 --- Bioactive polysaccharides in Lentinus edodes --- p.11 / Chapter 1.5.1.2 --- Bioactive polysaccharides in Ganoderma lucidum --- p.12 / Chapter 1.5.2 --- Immunomodulatory effects of polysaccharide-protein complexes --- p.12 / Chapter 1.5.2.1 --- Bioactive polysaccharide-protein complexes in Trametes versicolor --- p.13 / Chapter 1.5.3 --- Immunotherapeutic effects of mushroom polysaccharides --- p.14 / Chapter 1.6 --- Cell cycle and apoptosis --- p.14 / Chapter 1.6.1 --- Introduction of cell cycle --- p.14 / Chapter 1.6.2 --- Cell cycle regulation --- p.15 / Chapter 1.6.3 --- Antitumor effects through apoptotic gene regulation --- p.17 / Chapter 1.7 --- Mushroom sclerotium with antitumor activity --- p.20 / Chapter 1.7.1 --- Literature review on Pleurotus tuber-regium --- p.20 / Chapter 1.7.2 --- Literature review on Poria cocos --- p.22 / Chapter 1.7.3 --- Literature review on Polyporus rhinocerus --- p.23 / Chapter 1.8 --- Objectives --- p.23 / Chapter Chapter 2. --- Materials and Methods --- p.25 / Chapter 2.1 --- Materials --- p.25 / Chapter 2.1.1 --- Mushroom sclerotia --- p.25 / Chapter 2.1.2 --- Animal Model --- p.25 / Chapter 2.1.3 --- Cell lines --- p.27 / Chapter 2.2 --- Methods --- p.28 / Chapter 2.2.1 --- Extraction Scheme for mushroom sclerotia --- p.28 / Chapter 2.2.1.1 --- Hot water extraction only --- p.28 / Chapter 2.2.1.2 --- Sequential extraction scheme --- p.28 / Chapter 2.2.2 --- Measurement of monosaccharide profile --- p.31 / Chapter 2.2.2.1 --- Acid Depolymerisation --- p.31 / Chapter 2.2.2.2 --- Neutral Sugar Derivatization --- p.31 / Chapter 2.2.2.3 --- Gas Chromatography (GC) --- p.32 / Chapter 2.2.3 --- High Pressure Liquid Chromatography (HPLC) --- p.33 / Chapter 2.2.3.1 --- Size exclusion chromatography --- p.33 / Chapter 2.2.3.2 --- Anion exchange chromatography --- p.34 / Chapter 2.2.4 --- Linkage analysis by methylation --- p.34 / Chapter 2.2.4.1 --- Preparation of partially methylated polysaccharides --- p.34 / Chapter 2.2.4.2 --- Preparation of partially methylated alditol acetates (PMAAs) --- p.37 / Chapter 2.2.4.3 --- Gas chromatography-Mass spectrometry (GC-MS) analysis --- p.37 / Chapter 2.2.5 --- Determination of total sugar by phenol-sulphuric acid Method --- p.38 / Chapter 2.2.6 --- Determination of acidic sugars by measurement of uronic acid content --- p.39 / Chapter 2.2.7 --- Determination of protein content by Lowry-Folin method --- p.40 / Chapter 2.2.8 --- Chemical modification by carboxymethylation --- p.41 / Chapter 2.2.9 --- In vitro antitumor assay --- p.41 / Chapter 2.2.9.1 --- Trypan blue exclusion assay --- p.42 / Chapter 2.2.9.2 --- MTT Assay --- p.42 / Chapter 2.2.10 --- Cell cycle analysis by Flow Cytometry --- p.43 / Chapter 2.2.11 --- In vivo antitumor and immunomodulatory assay --- p.44 / Chapter 2.2.11.1 --- Measurement on tumor growth --- p.44 / Chapter 2.2.11.2 --- Blood sampling for immunostimulatory effects --- p.45 / Chapter 2.2.12 --- Mouse Cytokine Array --- p.45 / Chapter 2.2.13 --- Quantification of Mouse IL-13 by ELISA --- p.46 / Chapter 2.2.14 --- Enumeration of peritoneal cells --- p.47 / Chapter 2.2.15 --- Enumeration of splenocytes --- p.49 / Chapter 2.2.16 --- Statistical methods --- p.50 / Chapter Chapter 3. --- Results and Discussion --- p.51 / Chapter 3.1 --- Yield of crude mushroom sclerotial extracts --- p.51 / Chapter 3.2 --- Chemical composition of crude mushroom sclerotial extracts --- p.57 / Chapter 3.2.1 --- Total carbohydrate content --- p.57 / Chapter 3.2.2 --- Uronic acid content --- p.58 / Chapter 3.2.3 --- Soluble protein content --- p.58 / Chapter 3.3 --- Monosaccharide profiles of mushroom sclerotial extracts by GC --- p.60 / Chapter 3.4 --- Chromatographic analyses of mushroom sclerotial extracts --- p.65 / Chapter 3.4.1 --- Molecular weight profile by size exclusion chromatography (SEC) --- p.65 / Chapter 3.4.2 --- Charge distribution by ion exchange chromatography (IEC) --- p.73 / Chapter 3.5 --- Antitumor effects of mushroom sclerotial extracts from hot water extraction alone --- p.73 / Chapter 3.5.1 --- In vitro antiproliferative study by HL-60 --- p.73 / Chapter 3.5.2 --- In vitro antiproliferative study by MCF-7 --- p.74 / Chapter 3.5.3 --- In vivo antitumor study by BALB/c mice --- p.75 / Chapter 3.6 --- Antitumor effects of extracts from sequential extraction scheme --- p.76 / Chapter 3.6.1 --- In vitro antiproliferative study by HL-60 --- p.76 / Chapter 3.6.2 --- In vitro antiproliferative study by MCF-7 --- p.78 / Chapter 3.6.3 --- In vivo antitumor study by BALB/c mice --- p.80 / Chapter 3.7 --- Comparison of in vitro and in vivo activities of mushroom sclerotial extracts --- p.82 / Chapter 3.8 --- Dose-response relationship of hot water extract from PR on cancer cell lines --- p.85 / Chapter 3.8.1 --- In vitro dose-response antiproliferation of PR-W and PR-HWE on HL-60 --- p.85 / Chapter 3.8.2 --- In vitro dose-response antiproliferation of PR-W on K562 and S180 --- p.88 / Chapter 3.8.3 --- In vivo dose-response relationship of PR-W on S180 --- p.91 / Chapter 3.9 --- Flow cytometric analysis of PR-W on cancer cell lines --- p.92 / Chapter 3.9.1 --- Antiproliferative effect of PR-W on HL-60 --- p.92 / Chapter 3.9.2 --- Antiproliferative effect of PR-W on K562 --- p.95 / Chapter 3.9.3 --- Proposed mechanisms of cell cycle arrest by PR-W --- p.98 / Chapter 3.10 --- Host-mediated antitumor mechanism of PR-W --- p.100 / Chapter 3.10.1 --- Mouse cytokine array --- p.100 / Chapter 3.10.2 --- Quantification of IL-13 by ELISA --- p.105 / Chapter 3.10.3 --- Immunostimulatory effects of PR-W on mice --- p.109 / Chapter 3.11 --- Correlation between antitumor activity and structure of mushroom sclerotial extract from hot water extraction alone --- p.114 / Chapter Chapter 4. --- Conclusions and Future works --- p.118 / List of References --- p.121 / Related Publications --- p.142

Cheung Shu Yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 124-137). / Abstracts in English and Chinese. / Abstract (English) --- p.i / Abstract (Chinese) --- p.iii / Acknowledgements --- p.iv / Contents --- p.v / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Epidemiology of Breast Cancer --- p.1 / Chapter 1.1.1 --- Epidemiology of Breast Cancer in Females --- p.1 / Chapter 1.1.2 --- Incidence and Morality of Female Breast Cancer in Hong Kong --- p.2 / Chapter 1.1.3 --- Epidemiology of Breast Cancer in Males --- p.3 / Chapter 1.2 --- Risk Factors for Female Breast Cancer --- p.4 / Chapter 1.2.1 --- Genetic Risk Factors --- p.4 / Chapter 1.2.2 --- Hormonal Risk Factors --- p.6 / Chapter 1.2.2.1 --- Endogenous Hormonal Risk Factors --- p.7 / Chapter 1.2.2.2 --- Exogenous Hormonal Risk Factors --- p.8 / Chapter 1.2.3 --- Other Environmental Risk Factors --- p.9 / Chapter 1.3 --- Oncogenetic Basis of Female Breast Cancer --- p.10 / Chapter 1.4 --- Hormonal Basis of Female Breast Cancer --- p.12 / Chapter 1.4.1 --- Mechanisms of Hormone Action --- p.12 / Chapter 1.4.1.1 --- Estrogen and Progesterone --- p.12 / Chapter 1.4.1.2 --- Prolactin --- p.14 / Chapter 1.4.2 --- Hormonal Regulation of Normal Breast Development --- p.15 / Chapter 1.4.3 --- Hormonal Regulation of Breast Carcinogensis and Its Subsequent Progression --- p.17 / Chapter 1.4.3.1 --- Androgen --- p.17 / Chapter 1.4.3.2 --- Estrogen --- p.18 / Chapter 1.4.3.3 --- Progesterone --- p.20 / Chapter 1.4.3.4 --- Prolactin --- p.22 / Chapter 1.5 --- Animal Models for Breast Cancer --- p.23 / Chapter 1.5.1 --- Mouse Models --- p.24 / Chapter 1.5.2 --- Rat Models --- p.25 / Chapter 1.5.2.1 --- Carcinogen Induced Rat Models --- p.26 / Chapter 1.5.2.2 --- Hormone Induced Rat Models --- p.28 / Chapter 1.5.2.3 --- Spontaneously Developed Rat Models --- p.31 / Chapter 1.6 --- Aims of Study --- p.34 / Tables and Figures --- p.35 / Chapter Chapter 2 --- Materials and Methods / Chapter 2.1 --- Origin and Supply of Noble Rats --- p.37 / Chapter 2.2 --- Supply of Materials --- p.37 / Chapter 2.3 --- Induction of Mammary Tumors by Singe Dose of Chemical Carcinogens in Female Rats --- p.38 / Chapter 2.3.1 --- Induction by 7，12-Dimethylbenz[a]anthracene in Female Noble Rats --- p.38 / Chapter 2.3.2 --- Induction by N-Methyl-N-Nitrosourea in Female Sprague- Dawley Rats --- p.38 / Chapter 2.4 --- Induction of Mammary Tumors by Long-Term Treatments with Steroid Hormone --- p.39 / Chapter 2.4.1 --- Preparation of Steroid Hormone-filled Silastic® Tubings --- p.39 / Chapter 2.4.2 --- Surgical Implantation of Silastic® Tubings --- p.40 / Chapter 2.4.3 --- Protocols of Hormonal Treatments --- p.40 / Chapter 2.5 --- Collection of Spontaneously Developed Mammary Tumors in Noble Rats --- p.41 / Chapter 2.6 --- Transplantation of Spontaneously Developed Mammary Tumors into Noble Rats --- p.41 / Chapter 2.7 --- Bilateral Ovariectomy of Female Noble Rats bearing Spontaneously Developed Mammary Tumors --- p.42 / Chapter 2.8 --- Measurement of Mammary Tumor Growth --- p.43 / Chapter 2.9 --- Whole Mount Preparation of the Hormone-Treated Mammary Glands in Noble Rats --- p.44 / Chapter 2.10 --- Histological Examination of Mammary Gland and Tumors in Noble Rats --- p.45 / Chapter 2.11 --- Detection of Protein Expression of Hormone Receptors in Normal Mammary Glands and Mammary Tumors of Noble Rats --- p.45 / Chapter 2.11.1 --- Antibodies --- p.45 / Chapter 2.11.2 --- Immunohistochemistry --- p.47 / Chapter 2.11.3 --- "Protein extraction, SDS-PAGE and western blotting analysis" --- p.48 / Chapter Chapter 3 --- Results / Chapter 3.1 --- Gross Appearance of Mammary Tumors --- p.51 / Chapter 3.2 --- Incidence Rate of Mammary Tumors --- p.53 / Chapter 3.2.1 --- Spontaneously Developed Mammary Tumors in Noble Rats --- p.53 / Chapter 3.2.2 --- Hormone Induced Mammary Tumors in Female Noble Rats --- p.53 / Chapter 3.2.3 --- DMBA Induced Mammary Tumors in Female Noble Rats --- p.54 / Chapter 3.2.4 --- NMU Induced Mammary Tumors in Female SD Rats --- p.54 / Chapter 3.3 --- Histology of Normal and Lactating Mammary Glands in Female Noble Rats --- p.54 / Chapter 3.4 --- Histopathology of Mammary Tumors --- p.55 / Chapter 3.4.1 --- Histopathology of Spontaneously Developed Mammary Tumors in Noble Rats --- p.55 / Chapter 3.4.2 --- Histopathology of Hormone Induced Mammary Tumors in Female Noble Rats --- p.59 / Chapter 3.4.3 --- Histopathology of DMBA Induced Mammary Tumors in Female Noble Rats --- p.60 / Chapter 3.4.4 --- Histopathology of NMU Induced Mammary Tumors in Female SD Rat --- p.60 / Chapter 3.5 --- Whole Mount Preparation of Mammary Glands under Hormonal Treatments --- p.61 / Chapter 3.6 --- Effects of Bilateral Ovariectomy on the Growth of Spontaneously Developed Mammary Tumors --- p.61 / Chapter 3.7 --- Transplanability of the Spontaneously Developed Mammary Tumors in Noble Rats --- p.62 / Chapter 3.8 --- Examination of the Malignancy of Mammary Tumors by Immunohistochemical analysis of Epithelial Keratin Expression --- p.62 / Chapter 3.9 --- Immunohistochemical Analysis of Expression and Localization of Hormone Receptor Protein in Normal and Neoplastic Mammary Tissues of Female Noble Rats --- p.63 / Chapter 3.9.1 --- Expression and Localization of Hormone Receptors in Control Tissue --- p.63 / Chapter 3.9.2 --- Expression and Localization of Estrogen Receptor α --- p.64 / Chapter 3.9.3 --- Expression and Localization of Estrogen Receptor β --- p.65 / Chapter 3.9.4 --- Expression and Localization of Progesterone Receptor --- p.65 / Chapter 3.9.5 --- Expression and Localization of Androgen Receptor --- p.66 / Chapter 3.9.6 --- Expression and Localization of Prolactin Receptor --- p.66 / Chapter 3.10 --- Western Blot Analysis of Expression of Hormone Receptor Proteins in Normal and Neoplastic Mammary Tissues of Female Noble Rats - --- p.67 / Chapter 3.10.1 --- Expression of Estrogen Receptor α --- p.67 / Chapter 3.10.2 --- Expression of Estrogen Receptorβ --- p.68 / Chapter 3.10.3 --- Expression of Progesterone Receptor --- p.68 / Chapter 3.10.4 --- Expression of Androgen Receptor --- p.69 / Chapter 3.10.5 --- Expression of Prolactin Receptor --- p.69 / Figures and Tables --- p.71 / Chapter Chapter 4 --- Discussions / Chapter 4.1 --- Comparison of the Incidence Rate of Spontaneously developed Mammary Tumors in Noble Rats with the Previously Reported Incidence Rate --- p.102 / Chapter 4.2 --- Comparison of the Incidence rate of Spontaneously Developed Mammary Tumors in Noble Rats with the Incidence Rate in Other Rat Strains --- p.103 / Chapter 4.3 --- Crucial Factors Influencing the Incidence Rate of Spontaneously Developed Mammary Tumors in Noble Rats --- p.104 / Chapter 4.4 --- Comparison of the T+E2 Induced Mammary Tumors with the T+DES Induced Mammary Tumors in Female Noble Rats --- p.105 / Chapter 4.5 --- Comparison of the Incidence Rate & Latency Period of the Hormone Induced Mammary Tumors in Noble Rats with the Previously Reported Data --- p.106 / Chapter 4.6 --- Comparison of the Phenotypic Behaviors in Spontaneously Developed Mammary Tumors with the Hormone Induced Mammary Tumors in Female Noble Rats --- p.107 / Chapter 4.7 --- Comparison of the Behaviors of Carcinogen Induced Mammary Tumors with Spontaneously Developed & Hormone Induced Mammary Tumors in Female Noble Rats --- p.109 / Chapter 4.8 --- "Comparison of Expression Patterns of Hormone Receptor Proteins in Spontaneously Developed, Hormone Induced & Carcinogen Induced Mammary Tumors in Female Noble Rats" --- p.111 / Chapter 4.9 --- "Expressions of ERα & ERβ Proteins in Spontaneously Developed, Hormone Induced and Carcinogen Induced Mammary Tumors in Female Noble Rats" --- p.112 / Chapter 4.10 --- "Expressions of PR Proteins in Spontaneously Developed, Hormone Induced and Carcinogen Induced Mammary Tumors in Female Noble Rats" --- p.115 / Chapter 4.11 --- "Expressions of AR Proteins in Spontaneously Developed, Hormone Induced and Carcinogen Induced Mammary Tumors in Female Noble Rats" --- p.116 / Chapter 4.12 --- "Expressions of PRLR Proteins in Spontaneously Developed, Hormone Induced and Carcinogen Induced Mammary Tumors in Female Noble Rats" --- p.120 / Chapter Chapter 5 --- Conclusions --- p.123 / References --- p.124

The Met receptor tyrosine kinase (RTK) is expressed in the mammary gland under both normal and neoplastic conditions. Overexpression of the Met receptor is found in 15--20% of human breast cancers and is correlated with shortened disease-free interval and overall survival. In order to explore the role of dysregulated Met receptor signaling on the development of mammary tumors I have characterized a transgenic mouse model that expresses either wild type or a dysregulated Met receptor in the mammary epithelium under the control of the mouse mammary tumor virus promoter/enhancer (MMTV-Met). The Met receptor variants contained a mutation that results in decreased receptor ubiquitination and prolonged receptor signaling (Y1003F) or an activating mutation that was originally observed in patients with papillary renal carcinoma (M1250T) or both mutations (YF/MT). In vitro and in vivo transformation assays demonstrated that each mutation singly is weakly transforming, however, there was an additive effect on transformation when both mutations were present. This additive effect was observed in the transgenic mice where multiparous MMTV-Met-YF/MT mice developed tumors earlier and with much greater penetrance than did mice expressing either of the single mutants. This provides the first in vivo model that demonstrates a role for ubiquitination in suppression of transforming activity of an RTK. MMTV-Met-YF/MT tumors displayed a range of histological phenotypes but were mainly comprised of luminal lineage cells. Notably, MMTV-Met-M1250T tumors contained cells from both the basal and luminal populations, suggesting transformation of a progenitor cell. Progenitor cell transformation in RTK transgenic mouse models is uncommon and highlights distinct signaling differences and potentially lineage specificity of the two Met mutants. / Through assays of overexpression in vivo and inhibition in vitro, Met receptor signaling has been correlated with the development of the mammary gland. To examine the effects of loss of Met receptor signaling on mammary gland development I have utilized the Cre/LoxP1 recombination system to knock-out the Met receptor from the mammary epithelium. Mammary-specific Cre recombinase efficiently excised floxed DNA as visualized by activation of a beta-galactosidase reporter In Met+/+ glands, however, few beta-galactosidase positive cells are retained In the Mefl/fl glands and an intermediate number are retained in the Met fl/+ glands. This indicates that Met-null cells are selected against and supports a role for Met in the development of the mammary gland.