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Results: 1 to 10 of 96

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The Par3 polarity protein is an exocyst receptor essential for mammary cell survival.
Ahmed SM, Macara IG
(2017) Nat Commun 8: 14867
MeSH Terms: Animals, Apoptosis, Cadherins, Cell Adhesion Molecules, Cell Line, Cell Polarity, Cell Survival, Enzyme Activation, Epithelial Cells, Female, Gene Knockdown Techniques, Golgi Apparatus, Humans, Lysine, Mammary Glands, Animal, Models, Biological, PTEN Phosphohydrolase, Phosphatidylinositol Phosphates, Phosphorylation, Protein Domains, Proto-Oncogene Proteins c-akt, Vesicular Transport Proteins, rab GTP-Binding Proteins
Show Abstract · Added April 26, 2017
The exocyst is an essential component of the secretory pathway required for delivery of basolateral proteins to the plasma membranes of epithelial cells. Delivery occurs adjacent to tight junctions (TJ), suggesting that it recognizes a receptor at this location. However, no such receptor has been identified. The Par3 polarity protein associates with TJs but has no known function in membrane traffic. We now show that, unexpectedly, Par3 is essential for mammary cell survival. Par3 silencing causes apoptosis, triggered by phosphoinositide trisphosphate depletion and decreased Akt phosphorylation, resulting from failure of the exocyst to deliver basolateral proteins to the cortex. A small region of PAR3 binds directly to Exo70 and is sufficient for exocyst docking, membrane-protein delivery and cell survival. PAR3 lacking this domain can associate with the cortex but cannot support exocyst function. We conclude that Par3 is the long-sought exocyst receptor required for targeted membrane-protein delivery.
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23 MeSH Terms
Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells.
Dravis C, Spike BT, Harrell JC, Johns C, Trejo CL, Southard-Smith EM, Perou CM, Wahl GM
(2015) Cell Rep 12: 2035-48
MeSH Terms: Animals, Breast Neoplasms, Cell Culture Techniques, Cell Differentiation, Epithelial Cells, Epithelial-Mesenchymal Transition, Female, Fetus, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, Gene Expression Regulation, Neoplastic, Humans, Mammary Glands, Animal, Mammary Glands, Human, Mesenchymal Stem Cells, Mice, SOXE Transcription Factors, Signal Transduction, Spheroids, Cellular, Tumor Cells, Cultured
Show Abstract · Added September 28, 2015
To discover mechanisms that mediate plasticity in mammary cells, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor Sox10. Here, we show that Sox10 is specifically expressed in mammary cells exhibiting the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor competence whereas its overexpression increases stem/progenitor activity. Intriguingly, we also show that Sox10 overexpression causes mammary cells to undergo a mesenchymal transition. Consistent with these findings, Sox10 is preferentially expressed in stem- and mesenchymal-like breast cancers. These results demonstrate a signaling mechanism through which stem and mesenchymal states are acquired in mammary cells and suggest therapeutic avenues in breast cancers for which targeted therapies are currently unavailable.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis.
Morrison MM, Young CD, Wang S, Sobolik T, Sanchez VM, Hicks DJ, Cook RS, Brantley-Sieders DM
(2015) PLoS Genet 11: e1005291
MeSH Terms: Animals, Carrier Proteins, Cell Line, Cell Movement, Cell Survival, Female, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred C57BL, Mice, Transgenic, Morphogenesis, Multiprotein Complexes, Neoplasm Invasiveness, Neuropeptides, Organ Culture Techniques, Phosphorylation, Protein Kinase C-alpha, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, TOR Serine-Threonine Kinases, rac1 GTP-Binding Protein
Show Abstract · Added April 15, 2019
Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor deletion. Surprisingly, Akt re-activation was not sufficient to rescue cell survival or invasion, and modestly increased branching of mTORC2-impaired mammary epithelial cells (MECs) in culture and in vivo. However, another mTORC2 substrate, protein kinase C (PKC)-alpha, fully rescued mTORC2-impaired MEC branching, invasion, and survival, as well as branching morphogenesis in vivo. PKC-alpha-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary epithelial development during puberty, revealing a novel role for Rictor/mTORC2 in MEC survival and motility during branching morphogenesis through a PKC-alpha/Rac1-dependent mechanism.
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MeSH Terms
An epigenetic memory of pregnancy in the mouse mammary gland.
Dos Santos CO, Dolzhenko E, Hodges E, Smith AD, Hannon GJ
(2015) Cell Rep 11: 1102-9
MeSH Terms: Animals, DNA Methylation, Epigenesis, Genetic, Female, Mammary Glands, Animal, Mice, Mice, Inbred BALB C, Pregnancy, Real-Time Polymerase Chain Reaction, Transcriptome
Show Abstract · Added February 15, 2016
Pregnancy is the major modulator of mammary gland activity. It induces a tremendous expansion of the mammary epithelium and the generation of alveolar structures for milk production. Anecdotal evidence from multiparous humans indicates that the mammary gland may react less strongly to the first pregnancy than it does to subsequent pregnancies. Here, we verify that the mouse mammary gland responds more robustly to a second pregnancy, indicating that the gland retains a long-term memory of pregnancy. A comparison of genome-wide profiles of DNA methylation in isolated mammary cell types reveals substantial and long-lasting alterations. Since these alterations are maintained in the absence of the signal that induced them, we term them epigenetic. The majority of alterations in DNA methylation affect sites occupied by the Stat5a transcription factor and mark specific genes that are upregulated during pregnancy. We postulate that the epigenetic memory of a first pregnancy primes the activation of gene expression networks that promote mammary gland function in subsequent reproductive cycles. More broadly, our data indicate that physiological experience can broadly alter epigenetic states, functionally modifying the capacity of the affected cells to respond to later stimulatory events.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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10 MeSH Terms
Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance?
Williams MM, Cook RS
(2015) Oncotarget 6: 3519-30
MeSH Terms: Animals, Apoptosis, Breast, Breast Neoplasms, Female, Humans, Mammary Glands, Animal, Myeloid Cell Leukemia Sequence 1 Protein, Proto-Oncogene Proteins c-bcl-2
Show Abstract · Added April 15, 2019
Apoptosis, cell death executed by caspases, is essential to normal breast development and homeostasis. Pro-apoptotic and anti-apoptotic signals are tightly regulated in normal breast epithelial cells. Dysregulation of this balance is required for breast tumorigenesis and increases acquired resistance to treatments, including molecularly targeted therapies, radiation and chemotherapies. The pro-apoptotic or anti-apoptotic Bcl-2 family members interact with each other to maintain mitochondrial integrity and regulate cellular commitment to apoptosis. Among the anti-apoptotic Bcl-2 family members, Mcl-1 is uniquely regulated by numerous oncogenic signaling pathways. This review will focus on the role of Bcl-2 family proteins in normal breast development, breast tumorigenesis and acquired resistance to breast cancer treatment strategies, while highlighting Mcl-1 as a promising target to improve breast cancer tumor cell killing.
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Loss of the polarity protein PAR3 activates STAT3 signaling via an atypical protein kinase C (aPKC)/NF-κB/interleukin-6 (IL-6) axis in mouse mammary cells.
Guyer RA, Macara IG
(2015) J Biol Chem 290: 8457-68
MeSH Terms: Animals, Autocrine Communication, Cell Adhesion Molecules, Cells, Cultured, Cytokine Receptor gp130, Enzyme Activation, Epithelial Cells, Female, Interleukin-6, Mammary Glands, Animal, Mice, Inbred C3H, NF-kappa B, Phosphorylation, Protein Kinase C, Protein Processing, Post-Translational, STAT3 Transcription Factor, Signal Transduction
Show Abstract · Added April 10, 2018
PAR3 suppresses tumor growth and metastasis in vivo and cell invasion through matrix in vitro. We propose that PAR3 organizes and limits multiple signaling pathways and that inappropriate activation of these pathways occurs without PAR3. Silencing Pard3 in conjunction with oncogenic activation promotes invasion and metastasis via constitutive STAT3 activity in mouse models, but the mechanism for this is unknown. We now show that loss of PAR3 triggers increased production of interleukin-6, which induces STAT3 signaling in an autocrine manner. Activation of atypical protein kinase C ι/λ (aPKCι/λ) mediates this effect by stimulating NF-κB signaling and IL-6 expression. Our results suggest that PAR3 restrains aPKCι/λ activity and thus prevents aPKCι/λ from activating an oncogenic signaling network.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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Age- and pregnancy-associated DNA methylation changes in mammary epithelial cells.
Huh SJ, Clement K, Jee D, Merlini A, Choudhury S, Maruyama R, Yoo R, Chytil A, Boyle P, Ran FA, Moses HL, Barcellos-Hoff MH, Jackson-Grusby L, Meissner A, Polyak K
(2015) Stem Cell Reports 4: 297-311
MeSH Terms: Age Factors, Animals, Antigens, Surface, Cell Differentiation, Cluster Analysis, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Enhancer Elements, Genetic, Enzyme Activation, Epigenesis, Genetic, Epithelial Cells, Female, Gene Expression Profiling, Gene Expression Regulation, Histones, Immunophenotyping, Mammary Glands, Animal, Mice, Mice, Knockout, Organ Specificity, Phenotype, Pregnancy, Promoter Regions, Genetic, Sexual Maturation, Signal Transduction
Show Abstract · Added February 5, 2016
Postnatal mammary gland development and differentiation occur during puberty and pregnancy. To explore the role of DNA methylation in these processes, we determined the genome-wide DNA methylation and gene expression profiles of CD24(+)CD61(+)CD29(hi), CD24(+)CD61(+)CD29(lo), and CD24(+)CD61(-)CD29(lo) cell populations that were previously associated with distinct biological properties at different ages and reproductive stages. We found that pregnancy had the most significant effects on CD24(+)CD61(+)CD29(hi) and CD24(+)CD61(+)CD29(lo) cells, inducing distinct epigenetic states that were maintained through life. Integrated analysis of gene expression, DNA methylation, and histone modification profiles revealed cell-type- and reproductive-stage-specific changes. We identified p27 and TGFβ signaling as key regulators of CD24(+)CD61(+)CD29(lo) cell proliferation, based on their expression patterns and results from mammary gland explant cultures. Our results suggest that relatively minor changes in DNA methylation occur during luminal differentiation compared with the effects of pregnancy on CD24(+)CD61(+)CD29(hi) and CD24(+)CD61(+)CD29(lo) cells.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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26 MeSH Terms
Does FACS perturb gene expression?
Richardson GM, Lannigan J, Macara IG
(2015) Cytometry A 87: 166-75
MeSH Terms: Animals, Female, Flow Cytometry, Gene Expression, Gene Expression Profiling, Mammary Glands, Animal, Mice, Mice, Inbred C3H, MicroRNAs, Up-Regulation
Show Abstract · Added April 10, 2018
Fluorescence activated cell sorting is the technique most commonly used to separate primary mammary epithelial sub-populations. Many studies incorporate this technique before analyzing gene expression within specific cellular lineages. However, to our knowledge, no one has examined the effects of fluorescence activated cell sorting (FACS) separation on short-term transcriptional profiles. In this study, we isolated a heterogeneous mixture of cells from the mouse mammary gland. To determine the effects of the isolation and separation process on gene expression, we harvested RNA from the cells before enzymatic digestion, following enzymatic digestion, and following a mock FACS sort where the entire cohort of cells was retained. A strict protocol was followed to minimize disruption to the cells, and to ensure that no subpopulations were enriched or lost. Microarray analysis demonstrated that FACS causes minimal disruptions to gene expression patterns, but prior steps in the mammary cell isolation process are followed by upregulation of 18 miRNA's and rapid decreases in their predicted target transcripts. © 2015 International Society for Advancement of Cytometry.
© 2015 International Society for Advancement of Cytometry.
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Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution.
Stanford JC, Young C, Hicks D, Owens P, Williams A, Vaught DB, Morrison MM, Lim J, Williams M, Brantley-Sieders DM, Balko JM, Tonetti D, Earp HS, Cook RS
(2014) J Clin Invest 124: 4737-52
MeSH Terms: Animals, Apoptosis, Coculture Techniques, Cytokines, Female, Gene Expression, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, MCF-7 Cells, Male, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mice, Transgenic, Neoplasm Transplantation, Phagocytosis, Postpartum Period, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Signal Transduction, Tumor Burden, Up-Regulation, c-Mer Tyrosine Kinase
Show Abstract · Added February 12, 2015
Breast cancers that occur in women 2-5 years postpartum are more frequently diagnosed at metastatic stages and correlate with poorer outcomes compared with breast cancers diagnosed in young, premenopausal women. The molecular mechanisms underlying the malignant severity associated with postpartum breast cancers (ppBCs) are unclear but relate to stromal wound-healing events during postpartum involution, a dynamic process characterized by widespread cell death in milk-producing mammary epithelial cells (MECs). Using both spontaneous and allografted mammary tumors in fully immune-competent mice, we discovered that postpartum involution increases mammary tumor metastasis. Cell death was widespread, not only occurring in MECs but also in tumor epithelium. Dying tumor cells were cleared through receptor tyrosine kinase MerTK-dependent efferocytosis, which robustly induced the transcription of genes encoding wound-healing cytokines, including IL-4, IL-10, IL-13, and TGF-β. Animals lacking MerTK and animals treated with a MerTK inhibitor exhibited impaired efferocytosis in postpartum tumors, a reduction of M2-like macrophages but no change in total macrophage levels, decreased TGF-β expression, and a reduction of postpartum tumor metastasis that was similar to the metastasis frequencies observed in nulliparous mice. Moreover, TGF-β blockade reduced postpartum tumor metastasis. These data suggest that widespread cell death during postpartum involution triggers efferocytosis-induced wound-healing cytokines in the tumor microenvironment that promote metastatic tumor progression.
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23 MeSH Terms
Role of TGF-β signaling in generation of CD39+CD73+ myeloid cells in tumors.
Ryzhov SV, Pickup MW, Chytil A, Gorska AE, Zhang Q, Owens P, Feoktistov I, Moses HL, Novitskiy SV
(2014) J Immunol 193: 3155-64
MeSH Terms: 5'-Nucleotidase, Animals, Antigens, CD, Apyrase, Bone Marrow Cells, Carcinoma, Lewis Lung, Cell Differentiation, Cell Line, Tumor, Cell Movement, Female, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, T-Lymphocytes, Transforming Growth Factor beta, Tumor Microenvironment, Vascular Endothelial Growth Factor A
Show Abstract · Added December 3, 2014
There is growing evidence that generation of adenosine from ATP, which is mediated by the CD39/CD73 enzyme pair, predetermines immunosuppressive and proangiogenic properties of myeloid cells. We have previously shown that the deletion of the TGF-β type II receptor gene (Tgfbr2) expression in myeloid cells is associated with decreased tumor growth, suggesting protumorigenic effect of TGF-β signaling. In this study, we tested the hypothesis that TGF-β drives differentiation of myeloid-derived suppressor cells into protumorigenic terminally differentiated myeloid mononuclear cells (TDMMCs) characterized by high levels of cell-surface CD39/CD73 expression. We found that TDMMCs represent a major cell subpopulation expressing high levels of both CD39 and CD73 in the tumor microenvironment. In tumors isolated from mice with spontaneous tumor formation of mammary gland and conditional deletion of the type II TGF-β receptor in mammary epithelium, an increased level of TGF-β protein was associated with further increase in number of CD39(+)CD73(+) TDMMCs compared with MMTV-PyMT/TGFβRII(WT) control tumors with intact TGF-β signaling. Using genetic and pharmacological approaches, we demonstrated that the TGF-β signaling mediates maturation of myeloid-derived suppressor cells into TDMMCs with high levels of cell surface CD39/CD73 expression and adenosine-generating capacity. Disruption of TGF-β signaling in myeloid cells resulted in decreased accumulation of TDMMCs, expressing CD39 and CD73, and was accompanied by increased infiltration of T lymphocytes, reduced density of blood vessels, and diminished progression of both Lewis lung carcinoma and spontaneous mammary carcinomas. We propose that TGF-β signaling can directly induce the generation of CD39(+)CD73(+) TDMMCs, thus contributing to the immunosuppressive, proangiogenic, and tumor-promoting effects of this pleiotropic effector in the tumor microenvironment.
Copyright © 2014 by The American Association of Immunologists, Inc.
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24 MeSH Terms