Susanne Warrenfeltz - Academia.edu (original) (raw)
Papers by Susanne Warrenfeltz
Molecular Cancer Research, 2008
The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ... more The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ovarian cancer, are mediated by specific binding to its G protein -coupled receptor, the LH receptor (LHR). Activated LHR initiates second messenger responses, including cyclic AMP (cAMP) and inositol phosphate. Because cAMP increases expression of ErbB-2, a receptor tyrosine kinase whose overexpression in cancers correlates with poor survival, we hypothesized that LH may regulate ErbB-2 expression. Cell surface LHR expression in stable transformants of the ErbB-2 -overexpressing ovarian cancer cell line SKOV3 was confirmed by PCR and whole-cell ligand binding studies. Second messenger accumulation in the LHR-expressing cells confirmed signaling through Gs and Gq. Western blots of total protein revealed that LHR introduction up-regulated ErbB-2 protein expression 2-fold and this was further up-regulated in a time-and dose-dependent manner in response to LH. Forskolin and 8Br-cAMP also up-regulated ErbB-2 in both LHR-expressing and mock-transfected cells, indicating that regulation of ErbB-2 is a cAMP-mediated event. Kinase inhibitor studies indicated the involvement of protein kinase A -mediated, protein kinase C -mediated, epidermal growth factor receptor -mediated, and ErbB-2 -mediated mechanisms. The LH-induced up-regulation of ErbB-2 was insufficient to overcome the negative effects of LH on proliferation, invasion, and migration. A molecular signature for this nonaggressive phenotype was determined by Taqman array to include increased and decreased expression of genes encoding adhesion proteins and metalloproteinases, respectively. These data establish a role for LH and LHR in the regulation of ErbB-2 expression and suggest that, in some systems, ErbB-2 up-regulation alone is insufficient in producing a more aggressive phenotype. (Mol Cancer Res
Molecular and Cellular Endocrinology, 2010
The luteinizing hormone receptor (LHR), one of the three glycoprotein hormone receptors, is neces... more The luteinizing hormone receptor (LHR), one of the three glycoprotein hormone receptors, is necessary for critical reproductive processes, including gonadal steroidogenesis, oocyte maturation and ovulation, and male sex differentiation. Moreover, it has been postulated to contribute to certain neoplasms, particularly ovarian cancer. A member of the G protein-coupled receptor family, LHR contains a relatively large extracellular domain responsible for high affinity hormone binding; transmembrane activation then leads to G protein coupling and subsequent second messenger production. This review deals with recent advances in our understanding of LHR structure and structure-function relationships, as well as hormone-mediated changes in gene expression in ovarian cancer cells expressing LHR. Suggestions are also made for critical gaps that need to be filled as the field advances, including determination of the three-dimensional structure of inactive and active receptor, elucidation of the mechanism by which hormone binding to the extracellular domain triggers the activation of Gs, clarification of the putative roles of LHR in non-gonadal tissues, and the role, if any, of activated receptor in the development or progression of ovarian cancer.
Molecular cancer, Jan 7, 2004
Epithelial ovarian tumours exhibit a range of malignant potential, presenting distinct clinical p... more Epithelial ovarian tumours exhibit a range of malignant potential, presenting distinct clinical phenotypes. Improved knowledge of gene expression changes and functional pathways associated with these clinical phenotypes may lead to new treatment targets, markers for early detection and a better understanding of disease progression. Gene expression profiling (Affymetrix, U95Av2) was carried out on 18 ovarian tumours including benign adenomas, borderline adenocarcinomas of low malignant potential and malignant adenocarcinomas. Clustering the expression profiles of samples from patients not treated with chemotherapy prior to surgery effectively classified 92% of samples into their proper histopathological group. Some cancer samples from patients treated with chemotherapy prior to surgery clustered with the benign adenomas. Chemotherapy patients whose tumours exhibited benign-like expression patterns remained disease free for the duration of this study as indicated by continued normal s...
Nucleic Acids Research, 2013
EuPathDB (http://eupathdb.org) resources include 11 databases supporting eukaryotic pathogen geno... more EuPathDB (http://eupathdb.org) resources include 11 databases supporting eukaryotic pathogen genomic and functional genomic data, isolate data and phylogenomics. EuPathDB resources are built using the same infrastructure and provide a sophisticated search strategy system enabling complex interrogations of underlying data. Recent advances in EuPathDB resources include the design and implementation of a new data loading workflow, a new database supporting Piroplasmida (i.e. Babesia and Theileria), the addition of large amounts of new data and data types and the incorporation of new analysis tools. New data include genome sequences and annotation, strand-specific RNA-seq data, splice junction predictions (based on RNAseq), phosphoproteomic data, high-throughput phenotyping data, single nucleotide polymorphism data based on high-throughput sequencing (HTS) and expression quantitative trait loci data. New analysis tools enable users to search for DNA motifs and define genes based on their genomic colocation, view results from searches graphically (i.e. genes mapped to chromosomes or isolates displayed on a map) and analyze data from columns in result tables (word cloud and histogram summaries of column content). The manuscript herein describes updates to EuPathDB since the previous report published in NAR in 2010.
Molecular Cancer Research, 2008
The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ... more The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ovarian cancer, are mediated by specific binding to its G protein -coupled receptor, the LH receptor (LHR). Activated LHR initiates second messenger responses, including cyclic AMP (cAMP) and inositol phosphate. Because cAMP increases expression of ErbB-2, a receptor tyrosine kinase whose overexpression in cancers correlates with poor survival, we hypothesized that LH may regulate ErbB-2 expression. Cell surface LHR expression in stable transformants of the ErbB-2 -overexpressing ovarian cancer cell line SKOV3 was confirmed by PCR and whole-cell ligand binding studies. Second messenger accumulation in the LHR-expressing cells confirmed signaling through Gs and Gq. Western blots of total protein revealed that LHR introduction up-regulated ErbB-2 protein expression 2-fold and this was further up-regulated in a time-and dose-dependent manner in response to LH. Forskolin and 8Br-cAMP also up-regulated ErbB-2 in both LHR-expressing and mock-transfected cells, indicating that regulation of ErbB-2 is a cAMP-mediated event. Kinase inhibitor studies indicated the involvement of protein kinase A -mediated, protein kinase C -mediated, epidermal growth factor receptor -mediated, and ErbB-2 -mediated mechanisms. The LH-induced up-regulation of ErbB-2 was insufficient to overcome the negative effects of LH on proliferation, invasion, and migration. A molecular signature for this nonaggressive phenotype was determined by Taqman array to include increased and decreased expression of genes encoding adhesion proteins and metalloproteinases, respectively. These data establish a role for LH and LHR in the regulation of ErbB-2 expression and suggest that, in some systems, ErbB-2 up-regulation alone is insufficient in producing a more aggressive phenotype. (Mol Cancer Res
Biochemical and Biophysical Research Communications, 2004
Currently, there are no differentiation strategies for human embryonic stem cells (hESCs) that ef... more Currently, there are no differentiation strategies for human embryonic stem cells (hESCs) that efficiently produce one specific cell type, possibly because of lack of understanding of the genes that control signaling events prior to overt differentiation. sed HepG2 cell conditioned medium (MEDII), which induces early differentiation in mouse ES cells while retaining pluripotent markers, to query gene expression in hESCs. Treatment of adherent hESCs with 50% MEDII medium effected differentiation to a cell type with gene expression similar to primitive streak stage cells of mouse embryos. MEDII treatment up-regulates TDGF1 (Cripto), a gene essential for anterior-posterior axis and mesoderm formation in mouse embryos and a key component of the TGFB1/NODAL signaling pathway. LEFTYA, an antagonist of NODAL/TDGF1 signaling expressed in anterior visceral endoderm, is down-regulated with MEDII treatment, as is FST, an inhibitor of mesoderm induction via the related INHBE1 pathway. In summary, the TGFB1/ NODAL pathway is important for primitive-streak and mesoderm formation and in using MEDII, we present a means for generating an in vitro cell population that maintains pluripotent gene expression (POU5F1, NANOG) and SSEA-4 markers while regulating genes in the TGFB1/NODAL pathway, which may lead to more uniform formation of mesoderm in vitro.
BMC Cancer, 2011
Background: Since a substantial percentage of ovarian cancers express gonadotropin receptors and ... more Background: Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells. Methods: The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses. Results: Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic targets, may reflect a positive mediation of ovarian cancer growth.
Molecular Cancer Research, 2008
The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ... more The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ovarian cancer, are mediated by specific binding to its G protein -coupled receptor, the LH receptor (LHR). Activated LHR initiates second messenger responses, including cyclic AMP (cAMP) and inositol phosphate. Because cAMP increases expression of ErbB-2, a receptor tyrosine kinase whose overexpression in cancers correlates with poor survival, we hypothesized that LH may regulate ErbB-2 expression. Cell surface LHR expression in stable transformants of the ErbB-2 -overexpressing ovarian cancer cell line SKOV3 was confirmed by PCR and whole-cell ligand binding studies. Second messenger accumulation in the LHR-expressing cells confirmed signaling through Gs and Gq. Western blots of total protein revealed that LHR introduction up-regulated ErbB-2 protein expression 2-fold and this was further up-regulated in a time-and dose-dependent manner in response to LH. Forskolin and 8Br-cAMP also up-regulated ErbB-2 in both LHR-expressing and mock-transfected cells, indicating that regulation of ErbB-2 is a cAMP-mediated event. Kinase inhibitor studies indicated the involvement of protein kinase A -mediated, protein kinase C -mediated, epidermal growth factor receptor -mediated, and ErbB-2 -mediated mechanisms. The LH-induced up-regulation of ErbB-2 was insufficient to overcome the negative effects of LH on proliferation, invasion, and migration. A molecular signature for this nonaggressive phenotype was determined by Taqman array to include increased and decreased expression of genes encoding adhesion proteins and metalloproteinases, respectively. These data establish a role for LH and LHR in the regulation of ErbB-2 expression and suggest that, in some systems, ErbB-2 up-regulation alone is insufficient in producing a more aggressive phenotype. (Mol Cancer Res
Molecular and Cellular Endocrinology, 2010
The luteinizing hormone receptor (LHR), one of the three glycoprotein hormone receptors, is neces... more The luteinizing hormone receptor (LHR), one of the three glycoprotein hormone receptors, is necessary for critical reproductive processes, including gonadal steroidogenesis, oocyte maturation and ovulation, and male sex differentiation. Moreover, it has been postulated to contribute to certain neoplasms, particularly ovarian cancer. A member of the G protein-coupled receptor family, LHR contains a relatively large extracellular domain responsible for high affinity hormone binding; transmembrane activation then leads to G protein coupling and subsequent second messenger production. This review deals with recent advances in our understanding of LHR structure and structure-function relationships, as well as hormone-mediated changes in gene expression in ovarian cancer cells expressing LHR. Suggestions are also made for critical gaps that need to be filled as the field advances, including determination of the three-dimensional structure of inactive and active receptor, elucidation of the mechanism by which hormone binding to the extracellular domain triggers the activation of Gs, clarification of the putative roles of LHR in non-gonadal tissues, and the role, if any, of activated receptor in the development or progression of ovarian cancer.
Molecular cancer, Jan 7, 2004
Epithelial ovarian tumours exhibit a range of malignant potential, presenting distinct clinical p... more Epithelial ovarian tumours exhibit a range of malignant potential, presenting distinct clinical phenotypes. Improved knowledge of gene expression changes and functional pathways associated with these clinical phenotypes may lead to new treatment targets, markers for early detection and a better understanding of disease progression. Gene expression profiling (Affymetrix, U95Av2) was carried out on 18 ovarian tumours including benign adenomas, borderline adenocarcinomas of low malignant potential and malignant adenocarcinomas. Clustering the expression profiles of samples from patients not treated with chemotherapy prior to surgery effectively classified 92% of samples into their proper histopathological group. Some cancer samples from patients treated with chemotherapy prior to surgery clustered with the benign adenomas. Chemotherapy patients whose tumours exhibited benign-like expression patterns remained disease free for the duration of this study as indicated by continued normal s...
Nucleic Acids Research, 2013
EuPathDB (http://eupathdb.org) resources include 11 databases supporting eukaryotic pathogen geno... more EuPathDB (http://eupathdb.org) resources include 11 databases supporting eukaryotic pathogen genomic and functional genomic data, isolate data and phylogenomics. EuPathDB resources are built using the same infrastructure and provide a sophisticated search strategy system enabling complex interrogations of underlying data. Recent advances in EuPathDB resources include the design and implementation of a new data loading workflow, a new database supporting Piroplasmida (i.e. Babesia and Theileria), the addition of large amounts of new data and data types and the incorporation of new analysis tools. New data include genome sequences and annotation, strand-specific RNA-seq data, splice junction predictions (based on RNAseq), phosphoproteomic data, high-throughput phenotyping data, single nucleotide polymorphism data based on high-throughput sequencing (HTS) and expression quantitative trait loci data. New analysis tools enable users to search for DNA motifs and define genes based on their genomic colocation, view results from searches graphically (i.e. genes mapped to chromosomes or isolates displayed on a map) and analyze data from columns in result tables (word cloud and histogram summaries of column content). The manuscript herein describes updates to EuPathDB since the previous report published in NAR in 2010.
Molecular Cancer Research, 2008
The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ... more The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ovarian cancer, are mediated by specific binding to its G protein -coupled receptor, the LH receptor (LHR). Activated LHR initiates second messenger responses, including cyclic AMP (cAMP) and inositol phosphate. Because cAMP increases expression of ErbB-2, a receptor tyrosine kinase whose overexpression in cancers correlates with poor survival, we hypothesized that LH may regulate ErbB-2 expression. Cell surface LHR expression in stable transformants of the ErbB-2 -overexpressing ovarian cancer cell line SKOV3 was confirmed by PCR and whole-cell ligand binding studies. Second messenger accumulation in the LHR-expressing cells confirmed signaling through Gs and Gq. Western blots of total protein revealed that LHR introduction up-regulated ErbB-2 protein expression 2-fold and this was further up-regulated in a time-and dose-dependent manner in response to LH. Forskolin and 8Br-cAMP also up-regulated ErbB-2 in both LHR-expressing and mock-transfected cells, indicating that regulation of ErbB-2 is a cAMP-mediated event. Kinase inhibitor studies indicated the involvement of protein kinase A -mediated, protein kinase C -mediated, epidermal growth factor receptor -mediated, and ErbB-2 -mediated mechanisms. The LH-induced up-regulation of ErbB-2 was insufficient to overcome the negative effects of LH on proliferation, invasion, and migration. A molecular signature for this nonaggressive phenotype was determined by Taqman array to include increased and decreased expression of genes encoding adhesion proteins and metalloproteinases, respectively. These data establish a role for LH and LHR in the regulation of ErbB-2 expression and suggest that, in some systems, ErbB-2 up-regulation alone is insufficient in producing a more aggressive phenotype. (Mol Cancer Res
Biochemical and Biophysical Research Communications, 2004
Currently, there are no differentiation strategies for human embryonic stem cells (hESCs) that ef... more Currently, there are no differentiation strategies for human embryonic stem cells (hESCs) that efficiently produce one specific cell type, possibly because of lack of understanding of the genes that control signaling events prior to overt differentiation. sed HepG2 cell conditioned medium (MEDII), which induces early differentiation in mouse ES cells while retaining pluripotent markers, to query gene expression in hESCs. Treatment of adherent hESCs with 50% MEDII medium effected differentiation to a cell type with gene expression similar to primitive streak stage cells of mouse embryos. MEDII treatment up-regulates TDGF1 (Cripto), a gene essential for anterior-posterior axis and mesoderm formation in mouse embryos and a key component of the TGFB1/NODAL signaling pathway. LEFTYA, an antagonist of NODAL/TDGF1 signaling expressed in anterior visceral endoderm, is down-regulated with MEDII treatment, as is FST, an inhibitor of mesoderm induction via the related INHBE1 pathway. In summary, the TGFB1/ NODAL pathway is important for primitive-streak and mesoderm formation and in using MEDII, we present a means for generating an in vitro cell population that maintains pluripotent gene expression (POU5F1, NANOG) and SSEA-4 markers while regulating genes in the TGFB1/NODAL pathway, which may lead to more uniform formation of mesoderm in vitro.
BMC Cancer, 2011
Background: Since a substantial percentage of ovarian cancers express gonadotropin receptors and ... more Background: Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells. Methods: The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses. Results: Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic targets, may reflect a positive mediation of ovarian cancer growth.