ERBB4 Signaling In The Normal And Neoplastic Breast
Frank E Jones
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 5R01CA095783-07 from National Cancer Institute IRG: TCB
Abstract: The receptor tyrosine kinase ERBB4 has unique activities in the breast. For example, the other three ERBB-family members, namely EGFR, ERBB2/HER2/Neu, and ERBB3, directly contribute to aggressive breast cancer. Despite providing an essential function during lactation, ERBB4 expression is selectively extinguished during the progression of breast cancer. Significantly, ERBB4 functions as a pro-apoptotic BH3-only protein, of the BCL-2 family, specifically inducing apoptosis of malignant but not normal breast epithelium; thus providing a mechanistic explanation for the selective loss of ERBB4 expression in breast carcinomas. In normal breast epithelium, ERBB4 is a nuclear protein and activates milk-gene expression by functioning as a nuclear chaperone for the transcription factor, STAT5A. These divergent cellular responses to ERBB4 require proteolytic processing and subsequent release from the cell membrane the ERBB4 endodomain. Interestingly, the ERBB4 endodomain harbors the nuclear localization signal essential for stimulation of milk-gene expression and the pro-apoptotic BH3 domain. These observations support the hypothesis that novel signaling pathways mediated by the membrane-released ERBB4 endodomain regulate divergent ERBB4 activities in the normal and neoplastic breast. The following specific aims were designed to test this hypothesis Aim 1) Test the hypothesis that ERBB4 endodomain signaling directly contributes to breast development; Aim 2) Test the hypothesis that novel STAT5A phosphorylation events modulate ERBB4 endodomain-stimulated gene expression; Aim 3) Test the hypothesis that BCL-2-farnily members directly regulate ERBB4-induced apoptosis. The experiments described in this proposal are designed to provide a thorough analysis of nuclear and cytosolic ERBB4 endodomain signaling in the normal and neoplastic breast, respectively. Molecular mechanisms of ERBB4 function in the normal breast integrated with mechanistic studies of ERBB4 cell killing of malignant cells will provide the necessary foundation to develop ERBB4 signaling as a highly specific therapeutic approach for the treatment of breast tumors while sparing normal breast cells.
Keywords: biological signal transduction, breast neoplasm, mammary gland, tumor suppressor protein, cell differentiation, enzyme activity, epidermal growth factor, gene mutation, genetic recombination, growth factor receptor, neoplasm /cancer genetics, oncogene, oncoprotein, protein protein interaction, protein tyrosine kinase, genetically modified animal, laboratory mouse
Project start date: 2001-09-21
Project end date: 2009-06-30
5R01CA095783-07 (2007): $249517
Sponsored Links Excellgen http://Excellgen.com
ERBB4 Signaling In The Normal And Neoplastic Breast
Frank E Jones
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 5R01CA095783-06 from National Cancer Institute IRG: TCB
Abstract: The receptor tyrosine kinase ERBB4 has unique activities in the breast. For example, the other three ERBB-family members, namely EGFR, ERBB2/HER2/Neu, and ERBB3, directly contribute to aggressive breast cancer. Despite providing an essential function during lactation, ERBB4 expression is selectively extinguished during the progression of breast cancer. Significantly, ERBB4 functions as a pro-apoptotic BH3-only protein, of the BCL-2 family, specifically inducing apoptosis of malignant but not normal breast epithelium; thus providing a mechanistic explanation for the selective loss of ERBB4 expression in breast carcinomas. In normal breast epithelium, ERBB4 is a nuclear protein and activates milk-gene expression by functioning as a nuclear chaperone for the transcription factor, STAT5A. These divergent cellular responses to ERBB4 require proteolytic processing and subsequent release from the cell membrane the ERBB4 endodomain. Interestingly, the ERBB4 endodomain harbors the nuclear localization signal essential for stimulation of milk-gene expression and the pro-apoptotic BH3 domain. These observations support the hypothesis that novel signaling pathways mediated by the membrane-released ERBB4 endodomain regulate divergent ERBB4 activities in the normal and neoplastic breast. The following specific aims were designed to test this hypothesis Aim 1) Test the hypothesis that ERBB4 endodomain signaling directly contributes to breast development; Aim 2) Test the hypothesis that novel STAT5A phosphorylation events modulate ERBB4 endodomain-stimulated gene expression; Aim 3) Test the hypothesis that BCL-2-farnily members directly regulate ERBB4-induced apoptosis. The experiments described in this proposal are designed to provide a thorough analysis of nuclear and cytosolic ERBB4 endodomain signaling in the normal and neoplastic breast, respectively. Molecular mechanisms of ERBB4 function in the normal breast integrated with mechanistic studies of ERBB4 cell killing of malignant cells will provide the necessary foundation to develop ERBB4 signaling as a highly specific therapeutic approach for the treatment of breast tumors while sparing normal breast cells.
Keywords: biological signal transduction, breast neoplasm, mammary gland, tumor suppressor protein, cell differentiation, enzyme activity, epidermal growth factor, gene mutation, genetic recombination, growth factor receptor, neoplasm /cancer genetics, oncogene, oncoprotein, protein protein interaction, protein tyrosine kinase, genetically modified animal, laboratory mouse
Project start date: 2001-09-21
Project end date: 2009-06-30
5R01CA095783-06 (2006): $252963
5R01CA095783-05 (2005): $263153
5R01CA095783-03 (2003): $221938
Grants awarded to Frank E Jones
ERBB4 Signaling In The Normal And Neoplastic Breast
Frank E Jones
Pathologyuniversity Of Colorado Denver
grants And Contracts, Mail Stop F428
aurora, Co 800450508
Grant 7R01CA095783-08 from National Cancer Institute IRG: TCB
Abstract: The receptor tyrosine kinase ERBB4 has unique activities in the breast. For example, the other three ERBB-family members, namely EGFR, ERBB2/HER2/Neu, and ERBB3, directly contribute to aggressive breast cancer. Despite providing an essential function during lactation, ERBB4 expression is selectively extinguished during the progression of breast cancer. Significantly, ERBB4 functions as a pro-apoptotic BH3-only protein, of the BCL-2 family, specifically inducing apoptosis of malignant but not normal breast epithelium; thus providing a mechanistic explanation for the selective loss of ERBB4 expression in breast carcinomas. In normal breast epithelium, ERBB4 is a nuclear protein and activates milk-gene expression by functioning as a nuclear chaperone for the transcription factor, STAT5A. These divergent cellular responses to ERBB4 require proteolytic processing and subsequent release from the cell membrane the ERBB4 endodomain. Interestingly, the ERBB4 endodomain harbors the nuclear localization signal essential for stimulation of milk-gene expression and the pro-apoptotic BH3 domain. These observations support the hypothesis that novel signaling pathways mediated by the membrane- released ERBB4 endodomain regulate divergent ERBB4 activities in the normal and neoplastic breast. The following specific aims were designed to test this hypothesis Aim 1) Test the hypothesis that ERBB4 endodomain signaling directly contributes to breast development; Aim 2) Test the hypothesis that novel STAT5A phosphorylation events modulate ERBB4 endodomain-stimulated gene expression; Aim 3) Test the hypothesis that BCL-2-farnily members directly regulate ERBB4-induced apoptosis. The experiments described in this proposal are designed to provide a thorough analysis of nuclear and cytosolic ERBB4 endodomain signaling in the normal and neoplastic breast, respectively. Molecular mechanisms ofERBB4 fimction in the normal breast integrated with mechanistic studies of ERBB4 cell killing of malignant cells will provide the necessary foundation to develop ERBB4 signaling as a highly specific therapeutic approach for the treatment of breast tumors while sparing normal breast cells
Project start date: 2001-09-21
Project end date: 2009-06-30
7R01CA095783-08 (2008): $262836
3R01CA095783-05S1 (2006): $110927
2R01CA095783-04 (2004): $259050
ERBB4 IN THE NORMAL AND NEOPLASTIC BREAST
Frank E Jones, Professor
Tulane University Of Louisiana, 6823 St Charles Ave, New Orleans, La 70118
Grant 7R01CA095783-10 from National Cancer Institute
Abstract: The ERBB/EGFR family member HER4/ERBB4 has critical functions during normal development and influences the progression of human cancer. Proteolytic processing of ERBB4 at the cell surface releases an independently signaling ERBB4 intracellular domain (4ICD) with multiple divergent cellular activities. On the one hand 4ICD translocates to the nucleus in response to estrogen and coactivates gene expression by selectively binding with estrogen receptor to a subset of estrogen response gene promoters. On the other hand an ERBB4 ligand, HRG, promotes 4ICD translocation to mitochondria where 4ICD induces tumor cell apoptosis by functioning as a novel BH3-only protein (proapoptotic members of the BCL-2 family). Despite experimental descriptions of novel 4ICD activities, this unique signaling paradigm remains to be substantiated in physiologically relevant biological systems. Nuclear 4ICD within mammary epithelium coincident with the essential contributions of ERBB4 to lactation supports the hypothesis that 4ICD contributes to mammopoesis. We also hypothesize that novel 4ICD signaling events regulate estrogen activity in breast tumor cells and mediate the response of breast cancer patients to endocrine therapy. We propose to test these related hypotheses by pursuing the following specific aims Using mice with mutant ERBB4 alleles that abolish proteolytic processing we propose to (Aim 1) identify the contribution of ERBB4 processing and 4ICD nuclear localization to mammary gland development. We propose to employ global gene expression and promoter binding assays to (Aim 2) identify the molecular basis of coupled 4ICD/ER? signaling contributing to breast tumor cell proliferation. Clinical studies suggest that women with tumors coexpressing ER? and ERBB4 fare better when treated with endocrine therapy then women lacking tumor ERBB4 expression. Our data demonstrates that the 4ICD BH3-only protein is a key regulator of tamoxifen response and extinguished breast tumor cell expression of 4ICD results in tamoxifen resistance. We propose to (Aim 3) test the hypothesis that tumor expression of ERBB4/4ICD can be used a marker to predict clinical response to tamoxifen. We predict that our results will represent the first physiologically relevant contribution to the emerging field of cell-surface receptor signaling to the nucleus and have a major impact on therapeutic decisions affecting over 70% of breast cancer patients. Results from the proposed experiments will stimulate an intellectual and experimental paradigm shift with an emphasis on ERBB4/4ICD as a critical regulator of tamoxifen response in breast cancer patients. Thus we predict that our results will impact the majority of breast cancer patients and lay the foundation for the development of ERBB4/4ICD as an important tumor marker predicting clinical response to tamoxifen. By extension ERBB4/4ICD expression will be used to guide therapeutic decisions with patients with ERBB4/ER(+) tumors benefiting from tamoxifen whereas patients with ERBB4(-)/ER(+) tumors would be better served with a clinical regimen where tamoxifen was augmented or supplanted by another therapeutic approach
Keywords: (Z)-2-[4(1, 2-diphenyl-1-butenyl)-phenoxyl]-N, N-dimethylethanamine; 1-p-beta-dimethylamino-ethoxyphenyl-trans-1, 2-diphenylbut-1-ene; APP Secretase; Affect; Alleles; Allelomorphs; Amyloid Precursor Protein Secretase; Apoptosis; Apoptosis Pathway; Apoptotic; Assay; B-Cell CLL/lymphoma 2; BCL-2 Protein; BCL2; BCL2 protein; BH3 Domain; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Body Tissues; Breast; Breast Cancer Cell; Breast Carcinoma; Breast Neoplasms; Breast Tumors; Cancer Patient; Cancer of Breast; Cancers; Cell Communication and Signaling; Cell Death, Programmed; Cell Growth in Number; Cell Multiplication; Cell Nucleus; Cell Proliferation; Cell Signaling; Cell Surface Receptors; Cell membrane; Cell surface; Cells; Cellular Oncogene; Cellular Proliferation; Chaperone; Clinical; Clinical Research; Clinical Study; Coupled; Cytoplasmic Membrane; Data; Development; EGF Receptor 3 Gene; EGFR; ERBB Protein; ERBB1; ERBB2; ERBB2 gene; ERBB3; ERBB3 gene; Endocrine Therapy; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epithelium; ErbB-4; ErbB4; ErbB4 gene; Estrogen Receptors; Estrogenic Agents; Estrogenic Compounds; Estrogens; Ethanamine, 2-(4-(1, 2-diphenyl-1-butenyl)phenoxy)-N, N-dimethyl-, (Z)-; Event; Family; Family member; Figs; Figs - dietary; Forecast of outcome; Foundations; Gene Expression; Genes; Genes, HER-2; Genes, HER2; Genes, erbB-2; Genes, neu; HER -2; HER-2; HER-4; HER1; HER2; HER2/neu; HER3; HER4; Hand; Hormonal Therapy; Human; Human Breast Cancer Cell; Human EGF Receptor 2 Gene; Human, General; Intracellular Communication and Signaling; L-Serine; L-Tyrosine; Lactation; Ligands; Malignant; Malignant - descriptor; Malignant Cell; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Malignant neoplasm of breast; Mammals, Mice; Mammary Cancer; Mammary Carcinoma; Mammary Glands, Human; Mammary Neoplasms; Mammary gland; Man (Taxonomy); Man, Modern; Marshal; Mediating; Membrane; Mice; Milk; Mitochondria; Molecular; Molecular Chaperones; Molecular Interaction; Murine; Mus; NDF/Heregulin Receptor Gene; NLS Peptide; Nuclear; Nuclear Localization Signal; Nuclear Localization Signal Peptide; Nuclear Protein; Nuclear Proteins; Nuclear Translocation; Nucleus; Oranges; PTK Receptors; Pathway interactions; Patients; Phenotype; Phosphorylation; Plasma Membrane; Process; Prognosis; Prolactin Receptor; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Protein Phosphorylation; Proteins; Proteolytic Clipping; Proteolytic Processing; Proto-Oncogenes; RTK; Receptor Protein; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Receptors, PRL; Regimen; Resistance; STAT5; STAT5A; STAT5A gene; Serine; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Staging; TAM; TKR1; TM-MKR; TYR; Tamoxifen; Testing; Therapeutic; Therapeutic Estrogen; Tissues; Transforming Growth Factor alpha Receptor; Transgenes; Transmembrane Receptor Protein Tyrosine Kinase; Tumor Cell; Tumor Markers; Tyrosine; Tyrosine Kinase Growth Factor Receptor; Tyrosine Kinase Linked Receptors; Tyrosine Kinase Receptors; Tyrosine, L-isomer; Woman; base; biological signal transduction; biological systems; c-ONC; c-erbB-1; c-erbB-1 Protein; c-erbB-2; c-erbB-2 Genes; c-erbB-2 Proto-Oncogenes; cancer cell; cell killing; design; designing; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; experiment; experimental research; experimental study; gene product; hormone therapy; malignancy; malignant breast neoplasm; mammary; mammary epithelium; mammary gland development; mammary tumor; member; membrane structure; mitochondrial; mutant; neoplasm/cancer; neoplastic; neoplastic cell; novel; outcome forecast; overexpression; para-Tyrosine; pathway; plasmalemma; proto-oncogene protein c-erbB-1; protooncogene; public health relevance; receptor; research study; resistant; response; secretase; transcription factor; tumor
Project start date: 2001-09-21
Project end date: 2014-04-30
Budget start date: 16-AUG-2010
Budget end date: 30-APR-2011
PFA/PA: PA-07-070
7R01CA095783-10 (2010): $264129
3R01CA095783-10S1 (2010): $46218
2R01CA095783-09 (2009): $269842
ErbB4 Signaling In The Normal And Neoplastic Breast
Frank E Jones
Biochemistrytulane University Of Louisiana
6823 St Charles Ave
new Orleans, La 70118
Grant 1R01CA095783-01 from National Cancer Institute IRG: PTHB
Abstract: In this application, the P.I. proposes to examine the role of ErbB4 signaling in the normal and neoplastic breast. Based on data from the ErbB4 transgenic mice showing the role of ErbB4 in lobuloalveolar development and the clinical data that ErbB4 expression is a positive prognostic factor in cancer, the P.I. hypothesizes that ErbB4 signaling plays a role in breast differentiation. To test this hypothesis, four specific aims are proposed 1) to determine the normal function of ErbB4 in the developing mouse breast using Cre-lox recombination at both ErbB4 alleles to generate mammary-specific ErbB4 loss-of-function mutations; 2) to identify signaling networks of the oncogene HRGalpha in the mouse breast with a HRGalpha-null mouse; 3) to use a novel yeast "three" hybrid assay to identify ErbB4 regulated signaling proteins in the breast; and 4) to determine if ErbB4 signaling antagonizes ErbB2-induced breast cancer in a mouse model. These experiments are expected to identify ErbB4 signaling networks and determine their roles in both normal and neoplastic breast development
Keywords: biological signal transduction, breast neoplasm, mammary gland, tumor suppressor protein cell differentiation, enzyme activity, epidermal growth factor, gene mutation, genetic recombination, growth factor receptor, neoplasm /cancer genetics, oncogene, oncoprotein, protein protein interaction, protein tyrosine kinase laboratory mouse, transgenic animal
Project start date: 2001-09-21
Project end date: 2004-08-31
1R01CA095783-01 (2001): $234226
Influence Of ErbB4 Activity On Metastatic Breast Cancer
Frank E Jones
Tulane University Of Louisiana 6823 St Charles Ave New Orleans, La 70118
Grant 5R01CA096717-05 from National Cancer Institute IRG: MEP
Abstract: Expression of three members of the ErbB-family of receptor tyrosine kinases, namely EGFR, ErbB2, and ErbB3 are associated with aggressive metastatic breast cancer. In contrast, to the mitogenic activities associated with the other three ErbB-family members, ErbB4 mediates breast epithelial differentiation and ErbB4 expression is selectively extinguished in advanced breast cancer. Furthermore, ErbB4-signaling has antiproliferative activity in breast cancer and actively curtails mitogenic signaling by the protooncogene and therapeutic target, ErbB2. Collectively, these observations support the hypothesis that ErbB4-induced differentiation pathways in breast cancer antagonize the activities of important breast oncogenes, including ErbB2. The following specific aims were designed to test this hypothesis. Aim 1) investigate the influence of constitutive active ErbB4 (ErbB4-CA) on differentiation and ErbB2-induced cellular proliferation in human breast cancer cell lines, Aim 2) develop a preclinical transgenic mouse model of ErbB4-CA overexpression and determine the impact of ErbB4-CA on normal breast development and ErbB2-induced metastatic breast cancer, Aim 3) develop an independent preclinical mouse model to investigate the influence of extinguished ErbB4-signaling on spontaneous and ErbB2-induced breast carcinogenesis and metastasis, Aim 4) support preclinical models by determining the association of ErbB4 expression with clinical outcome and oncogenic phospho-ErbB2 expression in human primary breast tumors. The experiments described in this proposal are designed to provide a thorough analysis of ErbB4 function in the developing breast and determine the influence of ErbB4 signaling on ErbB2-induced metastatic breast cancer. If evidence suggests that ErbB4 activity antagonizes the development and progression of metastatic breast cancer in these preclinical and clinical models, future experiments will be designed to investigate the role of ErbB4 as a putative tumor suppressor in breast cancer and by extension explore the efficacy of ErbB4 signaling pathways as therapeutic agents in breast cancer.
Keywords: breast neoplasm, neoplasm /cancer genetics, protein tyrosine kinase, receptor expression, biological signal transduction, carcinogenesis, cell differentiation, cell proliferation, gene induction /repression, gene interaction, genetic model, mammary gland, metastasis, model design /development, oncogene, pathologic process, reproductive development, cell line, clinical research, genetically modified animal, human tissue, immunocytochemistry, laboratory mouse, neoplastic cell
Project start date: 2003-07-01
Project end date: 2008-04-30
5R01CA096717-05 (2007): $310998
3R01CA096717-03S2 (2006): $40095
5R01CA096717-04 (2006): $320203
Sponsored Links Excellgen http://Excellgen.com
3R01CA096717-03S1 (2005): $63989
5R01CA096717-03 (2005): $324024
3R01CA096717-02S1 (2004): $58905
5R01CA096717-02 (2004): $326312
1R01CA096717-01A1 (2003): $323981
Frank E Jones
Tulane University Of Louisiana
Project start date: 2003-07-01
Project end date: 2010-04-30
Influence Of ErbB4 Activity On Metastatic Breast Cancer
Frank E Jones
Tulane University Of Louisiana
3R01CA096717-04S1 (2006): $64125
BODY HYPERTHERMIA BY EXTRACORPOREAL CIRCULATION IN PATIENTS WITH ADVANCED CANCER
Frank E Jones
Medical College Of Wisconsin 8701 Watertown Plank Rd Milwaukee, Wi 532260509
Grant 5M01RR000058-240154 from National Center For Research Resources
Keywords: CARDIOVASCULAR SURGERY, EXTRACORPOREAL CIRCULATION, NEOPLASTIC THERAPY, THERMOTHERAPY, THERAPY EVALUATION, NEOPLASTIC THERAPY, PALLIATIVE TREATMENT, HUMAN, CLINICAL
Sponsored Links Excellgen http://Excellgen.com