The Experts below are selected from a list of 88908 Experts worldwide ranked by ideXlab platform
Ming Tan - One of the best experts on this subject based on the ideXlab platform.
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immunoregulatory protein b7 h3 regulates Cancer Stem Cell enrichment and drug resistance through mvp mediated mek activation
Oncogene, 2019Co-Authors: Zixing Liu, Wenling Zhang, Joshua B Phillips, Ritu Arora, Steven Mcclellan, Jiangfeng Li, Jinhwan Kim, Robert W Sobol, Ming TanAbstract:B7-H3 is a tumor-promoting glycoprotein that is expressed at low levels in most normal tissues, but is overexpressed in various human Cancers which is associated with disease progression and poor patient outcome. Although numerous publications have reported the correlation between B7-H3 and Cancer progression in many types of Cancers, mechanistic studies on how B7-H3 regulates Cancer malignancy are rare, and the mechanisms underlying the role of B7-H3 in drug resistance are almost unknown. Here we report a novel finding that upregulation of B7-H3 increases the breast Cancer Stem Cell population and promotes Cancer development. Depletion of B7-H3 in breast Cancer significantly inhibits the Cancer Stem Cells. By immunoprecipitation and mass spectrometry, we found that B7-H3 is associated with the major vault protein (MVP) and activates MEK through MVP-enhancing B-RAF and MEK interaction. B7-H3 expression increases Stem Cell population by binding to MVP which regulates the activation of the MAPK kinase pathway. Depletion of MVP blocks the activation of MEK induced by B7-H3 and dramatically inhibits B7-H3 induced Stem Cells. This study reports novel functions of B7-H3 in regulating breast Cancer Stem Cell enrichment. The novel mechanism for B7-H3-induced Stem Cell propagation by regulating MVP/MEK signaling axis independent of the classic Ras pathway may have important implications in the development of strategies for overcoming Cancer Cell resistance to chemotherapy.
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immunoregulatory protein b7 h3 regulates Cancer Stem Cell enrichment and drug resistance through mvp mediated mek activation
Oncogene, 2019Co-Authors: Zixing Liu, Wenling Zhang, Joshua B Phillips, Ritu Arora, Steven Mcclellan, Jinhwan Kim, Robert W Sobol, Ming TanAbstract:B7-H3 is a tumor-promoting glycoprotein that is expressed at low levels in most normal tissues, but is overexpressed in various human Cancers which is associated with disease progression and poor patient outcome. Although numerous publications have reported the correlation between B7-H3 and Cancer progression in many types of Cancers, mechanistic studies on how B7-H3 regulates Cancer malignancy are rare, and the mechanisms underlying the role of B7-H3 in drug resistance are almost unknown. Here we report a novel finding that upregulation of B7-H3 increases the breast Cancer Stem Cell population and promotes Cancer development. Depletion of B7-H3 in breast Cancer significantly inhibits the Cancer Stem Cells. By immunoprecipitation and mass spectrometry, we found that B7-H3 is associated with the major vault protein (MVP) and activates MEK through MVP-enhancing B-RAF and MEK interaction. B7-H3 expression increases Stem Cell population by binding to MVP which regulates the activation of the MAPK kinase pathway. Depletion of MVP blocks the activation of MEK induced by B7-H3 and dramatically inhibits B7-H3 induced Stem Cells. This study reports novel functions of B7-H3 in regulating breast Cancer Stem Cell enrichment. The novel mechanism for B7-H3-induced Stem Cell propagation by regulating MVP/MEK signaling axis independent of the classic Ras pathway may have important implications in the development of strategies for overcoming Cancer Cell resistance to chemotherapy.
Zixing Liu - One of the best experts on this subject based on the ideXlab platform.
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immunoregulatory protein b7 h3 regulates Cancer Stem Cell enrichment and drug resistance through mvp mediated mek activation
Oncogene, 2019Co-Authors: Zixing Liu, Wenling Zhang, Joshua B Phillips, Ritu Arora, Steven Mcclellan, Jiangfeng Li, Jinhwan Kim, Robert W Sobol, Ming TanAbstract:B7-H3 is a tumor-promoting glycoprotein that is expressed at low levels in most normal tissues, but is overexpressed in various human Cancers which is associated with disease progression and poor patient outcome. Although numerous publications have reported the correlation between B7-H3 and Cancer progression in many types of Cancers, mechanistic studies on how B7-H3 regulates Cancer malignancy are rare, and the mechanisms underlying the role of B7-H3 in drug resistance are almost unknown. Here we report a novel finding that upregulation of B7-H3 increases the breast Cancer Stem Cell population and promotes Cancer development. Depletion of B7-H3 in breast Cancer significantly inhibits the Cancer Stem Cells. By immunoprecipitation and mass spectrometry, we found that B7-H3 is associated with the major vault protein (MVP) and activates MEK through MVP-enhancing B-RAF and MEK interaction. B7-H3 expression increases Stem Cell population by binding to MVP which regulates the activation of the MAPK kinase pathway. Depletion of MVP blocks the activation of MEK induced by B7-H3 and dramatically inhibits B7-H3 induced Stem Cells. This study reports novel functions of B7-H3 in regulating breast Cancer Stem Cell enrichment. The novel mechanism for B7-H3-induced Stem Cell propagation by regulating MVP/MEK signaling axis independent of the classic Ras pathway may have important implications in the development of strategies for overcoming Cancer Cell resistance to chemotherapy.
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immunoregulatory protein b7 h3 regulates Cancer Stem Cell enrichment and drug resistance through mvp mediated mek activation
Oncogene, 2019Co-Authors: Zixing Liu, Wenling Zhang, Joshua B Phillips, Ritu Arora, Steven Mcclellan, Jinhwan Kim, Robert W Sobol, Ming TanAbstract:B7-H3 is a tumor-promoting glycoprotein that is expressed at low levels in most normal tissues, but is overexpressed in various human Cancers which is associated with disease progression and poor patient outcome. Although numerous publications have reported the correlation between B7-H3 and Cancer progression in many types of Cancers, mechanistic studies on how B7-H3 regulates Cancer malignancy are rare, and the mechanisms underlying the role of B7-H3 in drug resistance are almost unknown. Here we report a novel finding that upregulation of B7-H3 increases the breast Cancer Stem Cell population and promotes Cancer development. Depletion of B7-H3 in breast Cancer significantly inhibits the Cancer Stem Cells. By immunoprecipitation and mass spectrometry, we found that B7-H3 is associated with the major vault protein (MVP) and activates MEK through MVP-enhancing B-RAF and MEK interaction. B7-H3 expression increases Stem Cell population by binding to MVP which regulates the activation of the MAPK kinase pathway. Depletion of MVP blocks the activation of MEK induced by B7-H3 and dramatically inhibits B7-H3 induced Stem Cells. This study reports novel functions of B7-H3 in regulating breast Cancer Stem Cell enrichment. The novel mechanism for B7-H3-induced Stem Cell propagation by regulating MVP/MEK signaling axis independent of the classic Ras pathway may have important implications in the development of strategies for overcoming Cancer Cell resistance to chemotherapy.
Max S Wicha - One of the best experts on this subject based on the ideXlab platform.
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notch pathway activity identifies Cells with Cancer Stem Cell like properties and correlates with worse survival in lung adenocarcinoma
Clinical Cancer Research, 2013Co-Authors: Khaled A Hassan, Hasan Korkaya, Luo Wang, Guoan Chen, Ivan Maillard, David G Beer, Gregory P Kalemkerian, Max S WichaAbstract:Purpose: The Cancer Stem Cell theory postulates that tumors contain a subset of Cells with Stem Cell properties of self-renewal, differentiation, and tumor initiation. The purpose of this study is to determine the role of Notch activity in identifying lung Cancer Stem Cells. Experimental Design: We investigated the role of Notch activity in lung adenocarcinoma using a Notch GFP reporter construct and a γ-secretase inhibitor (GSI), which inhibits Notch pathway activity. Results: Transduction of lung Cancer Cells with Notch GFP reporter construct identified a subset of Cells with high Notch activity (GFP-bright). GFP-bright Cells had the ability to form more tumor spheres in serum-free media and were able to generate both GFP-bright and GFP-dim (lower Notch activity) Cell populations. GFP-bright Cells were resistant to chemotherapy and were tumorigenic in serial xenotransplantation assays. Tumor xenografts of mice treated with GSI had decreased expression of downstream effectors of Notch pathway and failed to regenerate tumors upon reimplantation in NOD/SCID mice. Using multivariate analysis, we detected a statistically significant correlation between poor clinical outcome and Notch activity (reflected in increased Notch ligand expression or decreased expression of the negative modulators), in a group of 443 patients with lung adenocarcinoma. This correlation was further confirmed in an independent group of 89 patients with adenocarcinoma in which Hes-1 overexpression correlated with poor overall survival. Conclusions: Notch activity can identify lung Cancer Stem Cell–like population and its inhibition may be an appropriate target for treating lung adenocarcinoma. Clin Cancer Res; 19(8); 1972–80. ©2013 AACR .
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implications of Cancer Stem Cell theory for Cancer chemoprevention by natural dietary compounds
Journal of Nutritional Biochemistry, 2011Co-Authors: Yanyan Li, Max S Wicha, Steven J SchwartzAbstract:Abstract The emergence of Cancer Stem Cell theory has profound implications for Cancer chemoprevention and therapy. Cancer Stem Cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of antiCancer drugs targeting Cancer Stem Cells. Naturally occurring dietary compounds have received increasing attention in Cancer chemoprevention. The antiCancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect Cancer Stem Cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against Cancer Stem Cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of Cancer Stem Cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D 3 , are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast Cancer Stem Cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating Cells and breast Cancer Stem Cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of Cancer Stem Cells. This may enable us to discover more preventive strategies for Cancer management by reducing Cancer resistance and recurrence and improving patient survival.
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implications of the Cancer Stem Cell hypothesis for breast Cancer prevention and therapy
Journal of Clinical Oncology, 2008Co-Authors: Madhuri Kakarala, Max S WichaAbstract:Recent research in breast biology has provided support for the Cancer Stem-Cell hypothesis. Two important components of this hypothesis are that tumors originate in mammary Stem or progenitor Cells as a result of dysregulation of the normally tightly regulated process of self-renewal. As a result, tumors contain and are driven by a Cellular subcomponent that retains key Stem-Cell properties including self-renewal, which drives tumorigenesis and differentiation that contributes to Cellular heterogeneity. Advances in Stem-Cell technology have led to the identification of Stem Cells in normal and malignant breast tissue. The study of these Stem Cells has helped to elucidate the origin of the molecular complexity of human breast Cancer. The Cancer Stem-Cell hypothesis has important implications for early detection, prevention, and treatment of breast Cancer. Both hereditary and sporadic breast Cancers may develop through dysregulation of Stem-Cell self-renewal pathways. These aberrant Stem Cells may provide t...
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implications of the Cancer Stem Cell hypothesis for breast Cancer prevention and therapy
Journal of Clinical Oncology, 2008Co-Authors: Madhuri Kakarala, Max S WichaAbstract:Recent research in breast biology has provided support for the Cancer Stem-Cell hypothesis. Two important components of this hypothesis are that tumors originate in mammary Stem or progenitor Cells as a result of dysregulation of the normally tightly regulated process of self-renewal. As a result, tumors contain and are driven by a Cellular subcomponent that retains key Stem-Cell properties including self-renewal, which drives tumorigenesis and differentiation that contributes to Cellular heterogeneity. Advances in Stem-Cell technology have led to the identification of Stem Cells in normal and malignant breast tissue. The study of these Stem Cells has helped to elucidate the origin of the molecular complexity of human breast Cancer. The Cancer Stem-Cell hypothesis has important implications for early detection, prevention, and treatment of breast Cancer. Both hereditary and sporadic breast Cancers may develop through dysregulation of Stem-Cell self-renewal pathways. These aberrant Stem Cells may provide targets for the development of Cancer prevention strategies. Furthermore, because breast Cancer Stem Cells may be highly resistant to radiation and chemotherapy, the development of more effective therapies for this disease may require the effective targeting of this Cell population.
Carol A. Lange - One of the best experts on this subject based on the ideXlab platform.
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Posttranslationally modified progesterone receptors direct ligand-specific expression of breast Cancer Stem Cell-associated gene programs
Journal of Hematology & Oncology, 2017Co-Authors: Todd P. Knutson, Thu H. Truong, Nicholas J. Brady, Megan E. Sullivan, Ganesh Raj, Kathryn L. Schwertfeger, Carol A. LangeAbstract:Background Estrogen and progesterone are potent breast mitogens. In addition to steroid hormones, multiple signaling pathways input to estrogen receptor (ER) and progesterone receptor (PR) actions via posttranslational events. Protein kinases commonly activated in breast Cancers phosphorylate steroid hormone receptors (SRs) and profoundly impact their activities. Methods To better understand the role of modified PRs in breast Cancer, we measured total and phospho-Ser294 PRs in 209 human breast tumors represented on 2754 individual tissue spots within a tissue microarray and assayed the regulation of this site in human tumor explants cultured ex vivo. To complement this analysis, we assayed PR target gene regulation in T47D luminal breast Cancer models following treatment with progestin (promegestone; R5020) and antiprogestins (mifepristone, onapristone, or aglepristone) in conditions under which the receptor is regulated by Lys388 SUMOylation (K388 intact) or is SUMO-deficient (via K388R mutation to mimic persistent Ser294 phosphorylation). Selected phospho-PR-driven target genes were validated by qRT-PCR and following RUNX2 shRNA knockdown in breast Cancer Cell lines. Primary and secondary mammosphere assays were performed to implicate phospho-Ser294 PRs, epidermal growth factor signaling, and RUNX2 in breast Cancer Stem Cell biology. Results Phospho-Ser294 PR species were abundant in a majority (54%) of luminal breast tumors, and PR promoter selectivity was exquisitely sensitive to posttranslational modifications. Phospho-PR expression and target gene programs were significantly associated with invasive lobular carcinoma (ILC). Consistent with our finding that activated phospho-PRs undergo rapid ligand-dependent turnover, unique phospho-PR gene signatures were most prevalent in breast tumors clinically designated as PR-low to PR-null (luminal B) and included gene sets associated with Cancer Stem Cell biology ( HER2 , PAX2 , AHR , AR , RUNX ). Validation studies demonstrated a requirement for RUNX2 in the regulation of selected phospho-PR target genes ( SLC37A2 ). In vitro mammosphere formation assays support a role for phospho-Ser294-PRs via growth factor (EGF) signaling as well as RUNX2 as potent drivers of breast Cancer Stem Cell fate. Conclusions We conclude that PR Ser294 phosphorylation is a common event in breast Cancer progression that is required to maintain breast Cancer Stem Cell fate, in part via cooperation with growth factor-initiated signaling pathways and key phospho-PR target genes including SLC37A2 and RUNX2 . Clinical measurement of phosphorylated PRs should be considered a useful marker of breast tumor Stem Cell potential. Alternatively, unique phospho-PR target gene sets may provide useful tools with which to identify patients likely to respond to selective PR modulators that block PR Ser294 phosphorylation as part of rational combination (i.e., with antiestrogens) endocrine therapies designed to durably block breast Cancer recurrence.
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posttranslationally modified progesterone receptors direct ligand specific expression of breast Cancer Stem Cell associated gene programs
Journal of Hematology & Oncology, 2017Co-Authors: Todd P. Knutson, Thu H. Truong, Nicholas J. Brady, Megan E. Sullivan, Kathryn L. Schwertfeger, Ganesh V Raj, Carol A. LangeAbstract:Estrogen and progesterone are potent breast mitogens. In addition to steroid hormones, multiple signaling pathways input to estrogen receptor (ER) and progesterone receptor (PR) actions via posttranslational events. Protein kinases commonly activated in breast Cancers phosphorylate steroid hormone receptors (SRs) and profoundly impact their activities. To better understand the role of modified PRs in breast Cancer, we measured total and phospho-Ser294 PRs in 209 human breast tumors represented on 2754 individual tissue spots within a tissue microarray and assayed the regulation of this site in human tumor explants cultured ex vivo. To complement this analysis, we assayed PR target gene regulation in T47D luminal breast Cancer models following treatment with progestin (promegestone; R5020) and antiprogestins (mifepristone, onapristone, or aglepristone) in conditions under which the receptor is regulated by Lys388 SUMOylation (K388 intact) or is SUMO-deficient (via K388R mutation to mimic persistent Ser294 phosphorylation). Selected phospho-PR-driven target genes were validated by qRT-PCR and following RUNX2 shRNA knockdown in breast Cancer Cell lines. Primary and secondary mammosphere assays were performed to implicate phospho-Ser294 PRs, epidermal growth factor signaling, and RUNX2 in breast Cancer Stem Cell biology. Phospho-Ser294 PR species were abundant in a majority (54%) of luminal breast tumors, and PR promoter selectivity was exquisitely sensitive to posttranslational modifications. Phospho-PR expression and target gene programs were significantly associated with invasive lobular carcinoma (ILC). Consistent with our finding that activated phospho-PRs undergo rapid ligand-dependent turnover, unique phospho-PR gene signatures were most prevalent in breast tumors clinically designated as PR-low to PR-null (luminal B) and included gene sets associated with Cancer Stem Cell biology (HER2, PAX2, AHR, AR, RUNX). Validation studies demonstrated a requirement for RUNX2 in the regulation of selected phospho-PR target genes (SLC37A2). In vitro mammosphere formation assays support a role for phospho-Ser294-PRs via growth factor (EGF) signaling as well as RUNX2 as potent drivers of breast Cancer Stem Cell fate. We conclude that PR Ser294 phosphorylation is a common event in breast Cancer progression that is required to maintain breast Cancer Stem Cell fate, in part via cooperation with growth factor-initiated signaling pathways and key phospho-PR target genes including SLC37A2 and RUNX2. Clinical measurement of phosphorylated PRs should be considered a useful marker of breast tumor Stem Cell potential. Alternatively, unique phospho-PR target gene sets may provide useful tools with which to identify patients likely to respond to selective PR modulators that block PR Ser294 phosphorylation as part of rational combination (i.e., with antiestrogens) endocrine therapies designed to durably block breast Cancer recurrence.
Wenling Zhang - One of the best experts on this subject based on the ideXlab platform.
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immunoregulatory protein b7 h3 regulates Cancer Stem Cell enrichment and drug resistance through mvp mediated mek activation
Oncogene, 2019Co-Authors: Zixing Liu, Wenling Zhang, Joshua B Phillips, Ritu Arora, Steven Mcclellan, Jiangfeng Li, Jinhwan Kim, Robert W Sobol, Ming TanAbstract:B7-H3 is a tumor-promoting glycoprotein that is expressed at low levels in most normal tissues, but is overexpressed in various human Cancers which is associated with disease progression and poor patient outcome. Although numerous publications have reported the correlation between B7-H3 and Cancer progression in many types of Cancers, mechanistic studies on how B7-H3 regulates Cancer malignancy are rare, and the mechanisms underlying the role of B7-H3 in drug resistance are almost unknown. Here we report a novel finding that upregulation of B7-H3 increases the breast Cancer Stem Cell population and promotes Cancer development. Depletion of B7-H3 in breast Cancer significantly inhibits the Cancer Stem Cells. By immunoprecipitation and mass spectrometry, we found that B7-H3 is associated with the major vault protein (MVP) and activates MEK through MVP-enhancing B-RAF and MEK interaction. B7-H3 expression increases Stem Cell population by binding to MVP which regulates the activation of the MAPK kinase pathway. Depletion of MVP blocks the activation of MEK induced by B7-H3 and dramatically inhibits B7-H3 induced Stem Cells. This study reports novel functions of B7-H3 in regulating breast Cancer Stem Cell enrichment. The novel mechanism for B7-H3-induced Stem Cell propagation by regulating MVP/MEK signaling axis independent of the classic Ras pathway may have important implications in the development of strategies for overcoming Cancer Cell resistance to chemotherapy.
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immunoregulatory protein b7 h3 regulates Cancer Stem Cell enrichment and drug resistance through mvp mediated mek activation
Oncogene, 2019Co-Authors: Zixing Liu, Wenling Zhang, Joshua B Phillips, Ritu Arora, Steven Mcclellan, Jinhwan Kim, Robert W Sobol, Ming TanAbstract:B7-H3 is a tumor-promoting glycoprotein that is expressed at low levels in most normal tissues, but is overexpressed in various human Cancers which is associated with disease progression and poor patient outcome. Although numerous publications have reported the correlation between B7-H3 and Cancer progression in many types of Cancers, mechanistic studies on how B7-H3 regulates Cancer malignancy are rare, and the mechanisms underlying the role of B7-H3 in drug resistance are almost unknown. Here we report a novel finding that upregulation of B7-H3 increases the breast Cancer Stem Cell population and promotes Cancer development. Depletion of B7-H3 in breast Cancer significantly inhibits the Cancer Stem Cells. By immunoprecipitation and mass spectrometry, we found that B7-H3 is associated with the major vault protein (MVP) and activates MEK through MVP-enhancing B-RAF and MEK interaction. B7-H3 expression increases Stem Cell population by binding to MVP which regulates the activation of the MAPK kinase pathway. Depletion of MVP blocks the activation of MEK induced by B7-H3 and dramatically inhibits B7-H3 induced Stem Cells. This study reports novel functions of B7-H3 in regulating breast Cancer Stem Cell enrichment. The novel mechanism for B7-H3-induced Stem Cell propagation by regulating MVP/MEK signaling axis independent of the classic Ras pathway may have important implications in the development of strategies for overcoming Cancer Cell resistance to chemotherapy.
