The Experts below are selected from a list of 28995 Experts worldwide ranked by ideXlab platform
Rama Khokha - One of the best experts on this subject based on the ideXlab platform.
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progesterone drives mammary secretory differentiation via rankl mediated induction of elf5 in luminal progenitor Cells
Development, 2013Co-Authors: Heather J Lee, David Gallegoortega, Anita Ledger, Daniel Schramek, Purna A Joshi, Maria M Szwarc, Christina Cho, John P Lydon, Rama Khokha, Josef M PenningerAbstract:Progesterone-RankL paracrine signaling has been proposed as a driver of Stem Cell Expansion in the mammary gland, and Elf5 is essential for the differentiation of mammary epithelial progenitor Cells. We demonstrate that Elf5 expression is induced by progesterone and that Elf5 and progesterone cooperate to promote alveolar development. The progesterone receptor and Elf5 are expressed in a mutually exclusive pattern, and we identify RankL as the paracrine mediator of the effects of progesterone on Elf5 expression in CD61+ progenitor Cells and their consequent differentiation. Blockade of RankL action prevented progesterone-induced side branching and the Expansion of Elf5 + mature luminal Cells. These findings describe a mechanism by which steroid hormones can produce the Expansion of steroid hormone receptor-negative mammary epithelial Cells.
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progesterone induces adult mammary Stem Cell Expansion
Nature, 2010Co-Authors: Purna A Joshi, Hartland W Jackson, Alexander G Beristain, Marco A Di Grappa, Patricia A Mote, Christine L Clarke, John Stingl, Paul Waterhouse, Rama KhokhaAbstract:The ovarian hormones oestrogen and progesterone are involved in a complicated series of interactions in the mammary glands from the beginning of puberty to the menopause. Many of these changes are associated with Cell proliferation, and breast cancer can result when errors occur. Two studies in this issue examine the effects of oestrogen and progesterone on mouse mammary Stem Cell (MaSC) function. They find that MaSC numbers decrease in virgin mice in the absence of both hormones due to ovariectomy or drug blockade, but increase with oestrogen and progesterone treatment. In addition, both groups implicate RANKL, a progesterone target known to be involved in bone remodelling and mammary gland formation, as an intermediary in the MaSC response to progesterone. Reproductive history influences breast cancer risk but the Cellular mechanisms are unclear. Here it is shown that ovarian hormones regulate the size of the mammary Stem Cell pool in mice. The size of this pool increases when progesterone levels increase during the reproductive cycle. Progesterone probably regulates Stem Cell numbers through a paracrine mechanism involving induction of RANKL and Wnt in luminal Cells. Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density1,2. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown3,4,5. Mammary Stem Cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and syStemic regulation6. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-Cell-enriched CD49fhi Cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this Expansion. In aged mice, CD49fhi Cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal Cells probably provide Wnt4 and RANKL signals to basal Cells which in turn respond by upregulating their cognate receptors, transcriptional targets and Cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary Stem Cell niche during the reproductive cycle, where MaSCs are putative targets for Cell transformation events leading to breast cancer.
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progesterone induces adult mammary Stem Cell Expansion
Nature, 2010Co-Authors: Purna A Joshi, Hartland W Jackson, Alexander G Beristain, Marco A Di Grappa, Patricia A Mote, Christine L Clarke, John Stingl, Paul Waterhouse, Rama KhokhaAbstract:Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown. Mammary Stem Cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and syStemic regulation. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-Cell-enriched CD49fhi Cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this Expansion. In aged mice, CD49fhi Cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal Cells probably provide Wnt4 and RANKL signals to basal Cells which in turn respond by upregulating their cognate receptors, transcriptional targets and Cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary Stem Cell niche during the reproductive cycle, where MaSCs are putative targets for Cell transformation events leading to breast cancer.
Sergej Nowoshilow - One of the best experts on this subject based on the ideXlab platform.
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planar Cell polarity mediated induction of neural Stem Cell Expansion during axolotl spinal cord regeneration
eLife, 2015Co-Authors: Aida Rodrigo Albors, Akira Tazaki, Fabian Rost, Sergej NowoshilowAbstract:Axolotls are uniquely able to mobilize neural Stem Cells to regenerate all missing regions of the spinal cord. How a neural Stem Cell under homeostasis converts after injury to a highly regenerative Cell remains unknown. Here, we show that during regeneration, axolotl neural Stem Cells repress neurogenic genes and reactivate a transcriptional program similar to embryonic neuroepithelial Cells. This dedifferentiation includes the acquisition of rapid Cell cycles, the switch from neurogenic to proliferative divisions, and the re-expression of planar Cell polarity (PCP) pathway components. We show that PCP induction is essential to reorient mitotic spindles along the anterior-posterior axis of elongation, and orthogonal to the Cell apical-basal axis. Disruption of this property results in premature neurogenesis and halts regeneration. Our findings reveal a key role for PCP in coordinating the morphogenesis of spinal cord outgrowth with the switch from a homeostatic to a regenerative Stem Cell that restores missing tissue.
Xuanmao Jiao - One of the best experts on this subject based on the ideXlab platform.
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ccr5 governs dna damage repair and breast cancer Stem Cell Expansion
Cancer Research, 2018Co-Authors: Xuanmao Jiao, Marco A Velascovelazquez, Min Wang, Hallgeir Rui, Amy R Peck, James E Korkola, Xuelian Chen, James B Duhadaway, Sandra L Guerrerorodriguez, Sankar AddyaAbstract:The functional significance of the chemokine receptor CCR5 in human breast cancer (BCa) epithelial Cells is poorly understood. Here we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5+ BCa epithelial Cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative BCa Cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced Cell killing mediated by DNA-damaging chemotherapeutic agents. Single Cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and Cell survival signaling. As CCR5 augments DNA repair and is re-expressed selectively on cancerous but not normal breast epithelial Cells, CCR5 inhibitors may enhance the tumor-specific activities of DDR-based treatments, allowing a dose reduction of standard chemotherapy and radiation.
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the canonical nf κb pathway governs mammary tumorigenesis in transgenic mice and tumor Stem Cell Expansion
Cancer Research, 2010Co-Authors: Manran Liu, Toshiyuki Sakamaki, Mathew C Casimiro, Nicole E Willmarth, Andrew A Quong, John O Ojeifo, Xuanmao Jiao, Wen Shuz Yeow, Sanjay Katiyar, Andrew L ShirleyAbstract:The role of mammary epithelial Cell (MEC) NF-κB in tumor progression in vivo is unknown, as murine NF-κB components and kinases either are required for murine survival or interfere with normal mammary gland development. As NF-κB inhibitors block both tumor-associated macrophages (TAM) and MEC NF-κB, the importance of MEC NF-κB to tumor progression in vivo remained to be determined. Herein, an MEC-targeted inducible transgenic inhibitor of NF-κB (IκBαSR) was developed in ErbB2 mammary oncomice. Inducible suppression of NF-κB in the adult mammary epithelium delayed the onset and number of new tumors. Within similar sized breast tumors, TAM and tumor neoangiogenesis was reduced. Coculture experiments demonstrated MEC NF-κB enhanced TAM recruitment. Genome-wide expression and proteomic analysis showed that IκBαSR inhibited tumor Stem Cell pathways. IκBαSR inhibited breast tumor Stem Cell markers in transgenic tumors, reduced Stem Cell Expansion in vitro, and repressed expression of Nanog and Sox2 in vivo and in vitro. MEC NF-κB contributes to mammary tumorigenesis. As we show that NF-κB contributes to Expansion of breast tumor Stem Cells and heterotypic signals that enhance TAM and vasculogenesis, these processes may contribute to NF-κB-dependent mammary tumorigenesis.
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c jun induces mammary epithelial Cellular invasion and breast cancer Stem Cell Expansion
Journal of Biological Chemistry, 2010Co-Authors: Xuanmao Jiao, Manran Liu, Nicole E Willmarth, Sanjay Katiyar, Neal Flomenberg, Michael P Lisanti, Richard G PestellAbstract:The molecular mechanisms governing breast tumor Cellular self-renewal contribute to breast cancer progression and therapeutic resistance. The ErbB2 oncogene is overexpressed in approximately 30% of human breast cancers. c-Jun, the first Cellular proto-oncogene, is overexpressed in human breast cancer. However, the role of endogenous c-Jun in mammary tumor progression is unknown. Herein, transgenic mice expressing the mammary gland-targeted ErbB2 oncogene were crossed with c-jun(f/f) transgenic mice to determine the role of endogenous c-Jun in mammary tumor invasion and Stem Cell function. The excision of c-jun by Cre recombinase reduced Cellular migration, invasion, and mammosphere formation of ErbB2-induced mammary tumors. Proteomic analysis identified a subset of secreted proteins (Stem Cell factor (SCF) and CCL5) induced by ErbB2 expression that were dependent upon endogenous c-Jun expression. SCF and CCL5 were identified as transcriptionally induced by c-Jun. CCL5 rescued the c-Jun-deficient breast tumor Cellular invasion phenotype. SCF rescued the c-Jun-deficient mammosphere production. Endogenous c-Jun thus contributes to ErbB2-induced mammary tumor Cell invasion and self-renewal.
Purna A Joshi - One of the best experts on this subject based on the ideXlab platform.
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progesterone drives mammary secretory differentiation via rankl mediated induction of elf5 in luminal progenitor Cells
Development, 2013Co-Authors: Heather J Lee, David Gallegoortega, Anita Ledger, Daniel Schramek, Purna A Joshi, Maria M Szwarc, Christina Cho, John P Lydon, Rama Khokha, Josef M PenningerAbstract:Progesterone-RankL paracrine signaling has been proposed as a driver of Stem Cell Expansion in the mammary gland, and Elf5 is essential for the differentiation of mammary epithelial progenitor Cells. We demonstrate that Elf5 expression is induced by progesterone and that Elf5 and progesterone cooperate to promote alveolar development. The progesterone receptor and Elf5 are expressed in a mutually exclusive pattern, and we identify RankL as the paracrine mediator of the effects of progesterone on Elf5 expression in CD61+ progenitor Cells and their consequent differentiation. Blockade of RankL action prevented progesterone-induced side branching and the Expansion of Elf5 + mature luminal Cells. These findings describe a mechanism by which steroid hormones can produce the Expansion of steroid hormone receptor-negative mammary epithelial Cells.
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progesterone induces adult mammary Stem Cell Expansion
Nature, 2010Co-Authors: Purna A Joshi, Hartland W Jackson, Alexander G Beristain, Marco A Di Grappa, Patricia A Mote, Christine L Clarke, John Stingl, Paul Waterhouse, Rama KhokhaAbstract:The ovarian hormones oestrogen and progesterone are involved in a complicated series of interactions in the mammary glands from the beginning of puberty to the menopause. Many of these changes are associated with Cell proliferation, and breast cancer can result when errors occur. Two studies in this issue examine the effects of oestrogen and progesterone on mouse mammary Stem Cell (MaSC) function. They find that MaSC numbers decrease in virgin mice in the absence of both hormones due to ovariectomy or drug blockade, but increase with oestrogen and progesterone treatment. In addition, both groups implicate RANKL, a progesterone target known to be involved in bone remodelling and mammary gland formation, as an intermediary in the MaSC response to progesterone. Reproductive history influences breast cancer risk but the Cellular mechanisms are unclear. Here it is shown that ovarian hormones regulate the size of the mammary Stem Cell pool in mice. The size of this pool increases when progesterone levels increase during the reproductive cycle. Progesterone probably regulates Stem Cell numbers through a paracrine mechanism involving induction of RANKL and Wnt in luminal Cells. Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density1,2. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown3,4,5. Mammary Stem Cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and syStemic regulation6. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-Cell-enriched CD49fhi Cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this Expansion. In aged mice, CD49fhi Cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal Cells probably provide Wnt4 and RANKL signals to basal Cells which in turn respond by upregulating their cognate receptors, transcriptional targets and Cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary Stem Cell niche during the reproductive cycle, where MaSCs are putative targets for Cell transformation events leading to breast cancer.
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progesterone induces adult mammary Stem Cell Expansion
Nature, 2010Co-Authors: Purna A Joshi, Hartland W Jackson, Alexander G Beristain, Marco A Di Grappa, Patricia A Mote, Christine L Clarke, John Stingl, Paul Waterhouse, Rama KhokhaAbstract:Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown. Mammary Stem Cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and syStemic regulation. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-Cell-enriched CD49fhi Cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this Expansion. In aged mice, CD49fhi Cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal Cells probably provide Wnt4 and RANKL signals to basal Cells which in turn respond by upregulating their cognate receptors, transcriptional targets and Cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary Stem Cell niche during the reproductive cycle, where MaSCs are putative targets for Cell transformation events leading to breast cancer.
Raymond N Dubois - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin e2 promotes colorectal cancer Stem Cell Expansion and metastasis in mice
Gastroenterology, 2015Co-Authors: Dingzhi Wang, Haiyan Sun, Lixia Guo, Raymond N DuboisAbstract:Background & Aims Inflammation may contribute to the formation, maintenance, and Expansion of cancer Stem Cells (CSCs), which have the capacity for self-renewal, differentiation, and resistance to cytotoxic agents. We investigated the effects of the inflammatory mediator prostaglandin E 2 (PGE 2 ) on colorectal CSC development and metastasis in mice and the correlation between levels of PGE 2 and CSC markers in human colorectal cancer (CRC) specimens. Methods Colorectal carcinoma specimens and matched normal tissues were collected from patients at the Mayo Clinic (Scottsdale, AZ) and analyzed by mass spectrometry and quantitative polymerase chain reaction. Human primary CRC Cells and mouse tumor Cells were isolated using microbeads or flow cytometry and analyzed for sphere-formation and by flow cytometry assays. LS-174T Cells were sorted by flow cytometry (for CD133 + CD44 + and CD133 - CD44 - Cells) and also used in these assays. NOD-scid IL-2Rγ -/- (NSG) mice were given cecal or subcutaneous injections of LS-174T or human primary CRC Cells. Apc Min/+ mice and NSG mice with orthotopic cecal tumors were given vehicle (controls), PGE 2 , celecoxib, and/or Ono-AE3-208. PGE 2 downstream signaling pathways were knocked down with small hairpin RNAs, expressed from lentiviral vectors in LS-174T Cells, or blocked with inhibitors in human primary CRC Cells. Results Levels of PGE 2 correlated with colonic CSC markers ( CD133 , CD44 , LRG5 , and SOX2 messenger RNAs) in human colorectal carcinoma samples. Administration of PGE 2 to Apc Min/+ mice increased tumor Stem Cells and tumor burden, compared with controls. NSG mice given PGE 2 had increased numbers of cecal CSCs and liver metastases compared with controls after intracecal injection of LS-174T or human primary CRC Cells. Alternatively, celecoxib, an inhibitor of prostaglandin-endoperoxide synthase 2, reduced polyp numbers in Apc Min/+ mice, liver metastasis in NSG mice with orthotopic tumors, and numbers of CSCs in Apc Min/+ and NSG mice. Inhibitors or knockdown of PGE 2 receptor 4 (EP4), phosphoinositide 3-kinase (PI3K) p85α, extraCellular signal-regulated kinase 1 (ERK1), or nuclear factor (NF)-κB reduced PGE 2 -induced sphere formation and Expansion of LS-174T and/or human primary CRC Cells. Knockdown of ERK1 or PI3K p85α also attenuated PGE 2 -induced activation of NF-κB in LS-174T Cells. An EP4 antagonist reduced the ability of PGE 2 to induce CSC Expansion in orthotopic tumors and to accelerate the formation of liver metastases. Knockdown experiments showed that NF-κB was required for PGE 2 induction of CSCs and metastasis in mice. Conclusions PGE 2 induces CSC Expansion by activating NF-κB, via EP4–PI3K and EP4–mitogen-activated protein kinase signaling, and promotes the formation of liver metastases in mice. The PGE 2 signaling pathway therefore might be targeted therapeutically to slow CSC Expansion and colorectal cancer progression.