Mammary Epithelium

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Keiko Miyoshi - One of the best experts on this subject based on the ideXlab platform.

  • inactivation of stat5 in mouse Mammary Epithelium during pregnancy reveals distinct functions in cell proliferation survival and differentiation
    Molecular and Cellular Biology, 2004
    Co-Authors: Yongzhi Cui, Keiko Miyoshi, Gertraud W Robinson, Greg Riedlinger, Wei Tang, Chuxia Deng, Lothar Hennighausen
    Abstract:

    This study explored the functions of the signal transducers and activators of transcription 5a and 5b (referred to as Stat5 here) during different stages of mouse Mammary gland development by using conditional gene inactivation. Mammary gland morphogenesis includes cell specification, proliferation and differentiation during pregnancy, cell survival and maintenance of differentiation throughout lactation, and cell death during involution. Stat5 is activated by prolactin, and its presence is mandatory for the proliferation and differentiation of Mammary Epithelium during pregnancy. To address the question of whether Stat5 is also necessary for the maintenance and survival of the differentiated Epithelium, the two genes were deleted at different time points. The 110-kb Stat5 locus in the mouse was bracketed with loxP sites, and its deletion was accomplished by using two Cre-expressing transgenic lines. Loss of Stat5 prior to pregnancy prevented epithelial proliferation and differentiation. Deletion of Stat5 during pregnancy, after Mammary Epithelium had entered Stat5-mediated differentiation, resulted in premature cell death, indicating that at this stage epithelial cell proliferation, differentiation, and survival require Stat5.

  • Loss of connexin 26 in Mammary Epithelium during early but not during late pregnancy results in unscheduled apoptosis and impaired development.
    Developmental biology, 2004
    Co-Authors: Celine Bry, Keiko Miyoshi, Gertraud W Robinson, Karen Maass, Klaus Willecke, Thomas Ott, Lothar Hennighausen
    Abstract:

    Gap junctions are intercellular channels that are formed by the protein family of connexins (Cxs). In Mammary tissue, Cx26 and Cx32 are present in the secretory Epithelium and Cx43 is localized in the myoEpithelium. The expression of Cx26 and Cx32 is induced during pregnancy and lactation, respectively, thus suggesting unique roles for them in the functional development of the gland. The requirement for these connexins was explored using several strains of genetically altered mice: mice with an inactivated Cx32 gene, mice in which the Cx43 gene had been replaced with the Cx32 gene (Cx43KI32 mice) and mice in which the Cx26 gene was specifically ablated in Mammary Epithelium at different stages of development using Cre-loxP-based recombination. Normal Mammary development was obtained in Cx32-null mice and in Cx43KI32 Mammary tissue. In contrast, loss of Cx26 in Mammary Epithelium before puberty resulted in abrogated lobulo-alveolar development and increased cell death during pregnancy, which was accompanied by impaired lactation. Loss of Cx26 in Mammary Epithelium during the later part of pregnancy did not adversely interfere with functional Mammary development. These results demonstrate that the presence of Cx26 is critical during early stages but not during the end of pregnancy when the tissue has completed functional differentiation. Cx26 is considered a tumor suppressor gene and Cx26-null Mammary tissue was evaluated after five pregnancies. No hyperproliferation or hyperplasia was observed, suggesting that Cx26 does not function as a tumor suppressor.

  • selective removal of the selenocysteine trna ser sec gene trsp in mouse Mammary Epithelium
    Molecular and Cellular Biology, 2003
    Co-Authors: Easwari Kumaraswamy, Keiko Miyoshi, Fanta Morgan, Gertraud W Robinson, Bradley A Carlson, Dan Su, Shulin Wang, Eileen Southon, Lino Tessarollo, Vadim N Gladyshev
    Abstract:

    Mice homozygous for an allele encoding the selenocysteine (Sec) tRNA[Ser]Sec gene (Trsp) flanked by loxP sites were generated. Cre recombinase-dependent removal of Trsp in these mice was lethal to embryos. To investigate the role of Trsp in mouse Mammary Epithelium, we deleted this gene by using transgenic mice carrying the Cre recombinase gene under control of the mouse Mammary tumor virus (MMTV) long terminal repeat or the whey acidic protein promoter. While both promoters target Cre gene expression to Mammary Epithelium, MMTV-Cre is also expressed in spleen and skin. Sec tRNA[Ser]Sec amounts were reduced by more than 70% in Mammary tissue with either transgene, while in skin and spleen, levels were reduced only with MMTV-Cre. The selenoprotein population was selectively affected with MMTV-Cre in breast and skin but not in the control tissue, kidney. Moreover, within affected tissues, expression of specific selenoproteins was regulated differently and often in a contrasting manner, with levels of Sep15 and the glutathione peroxidases GPx1 and GPx4 being substantially reduced. Expression of the tumor suppressor genes BRCA1 and p53 was also altered in a contrasting manner in MMTV-Cre mice, suggesting greater susceptibility to cancer and/or increased cell apoptosis. Thus, the conditional Trsp knockout mouse allows tissue-specific manipulation of Sec tRNA and selenoprotein expression, suggesting that this approach will provide a useful tool for studying the role of selenoproteins in health.

  • Activation of different Wnt/β-catenin signaling components in Mammary Epithelium induces transdifferentiation and the formation of pilar tumors
    Oncogene, 2002
    Co-Authors: Keiko Miyoshi, Masahiro Nozawa, Andrea Rosner, Christopher Byrd, Fanta Morgan, Esther Landesman-bollag, David C Seldin, Emmett V Schmidt, Makato M Taketo, Gertraud W Robinson
    Abstract:

    The Wnt/β-catenin signaling pathway controls cell fate and neoplastic transformation. Expression of an endogenous stabilized β-catenin (ΔE3 β-catenin) in Mammary Epithelium leads to the transdifferentiation into epidermis- and pilar-like structures. Signaling molecules in the canonical Wnt pathway upstream from β-catenin induce glandular tumors but it is not clear whether they also cause squamous transdifferentiation. To address this question we have now investigated Mammary Epithelium from transgenic mice that express activating molecules of the Wnt pathway: Wnt10b, Int2/Fgf3, CK2α, ΔE3 β-catenin, Cyclin D1, and dominant negative (dn) GSK3β. Cytokeratin 5 (CK5), which is expressed in both Mammary myoEpithelium and epidermis, and the epidermis-specific CK1 and CK6 were used as differentiation markers. Extensive squamous metaplasias and widespread expression of CK1 and CK6 were observed in ΔE3 β-catenin transgenic Mammary tissue. Wnt10b and Int2 transgenes also induced squamous metaplasias, but expression of CK1 and CK6 was sporadic. While CK5 expression in Wnt10b transgenic tissue was still confined to the lining cell layer, its expression in Int2 transgenic tissue was completely disorganized. In contrast, cytokeratin expression in CK2α, dnGSK3β and Cyclin D1 transgenic Mammary tissues was similar to that in ΔE3 β-catenin tissue. In support of transdifferentiation, expression of hard keratins specific for hair and nails was observed in pilar tumors. These results demonstrate that the activation of Wnt signaling components in Mammary Epithelium induces not only glandular tumors but also squamous differentiation, possibly by activating LEF-1, which is expressed in normal Mammary Epithelium.

  • activation of different wnt β catenin signaling components in Mammary Epithelium induces transdifferentiation and the formation of pilar tumors
    Oncogene, 2002
    Co-Authors: Masahiro Nozawa, Keiko Miyoshi, Andrea Rosner, Christopher Byrd, Fanta Morgan, David C Seldin, Emmett V Schmidt, Esther Landesmanbollag, Makato M Taketo
    Abstract:

    The Wnt/β-catenin signaling pathway controls cell fate and neoplastic transformation. Expression of an endogenous stabilized β-catenin (ΔE3 β-catenin) in Mammary Epithelium leads to the transdifferentiation into epidermis- and pilar-like structures. Signaling molecules in the canonical Wnt pathway upstream from β-catenin induce glandular tumors but it is not clear whether they also cause squamous transdifferentiation. To address this question we have now investigated Mammary Epithelium from transgenic mice that express activating molecules of the Wnt pathway: Wnt10b, Int2/Fgf3, CK2α, ΔE3 β-catenin, Cyclin D1, and dominant negative (dn) GSK3β. Cytokeratin 5 (CK5), which is expressed in both Mammary myoEpithelium and epidermis, and the epidermis-specific CK1 and CK6 were used as differentiation markers. Extensive squamous metaplasias and widespread expression of CK1 and CK6 were observed in ΔE3 β-catenin transgenic Mammary tissue. Wnt10b and Int2 transgenes also induced squamous metaplasias, but expression of CK1 and CK6 was sporadic. While CK5 expression in Wnt10b transgenic tissue was still confined to the lining cell layer, its expression in Int2 transgenic tissue was completely disorganized. In contrast, cytokeratin expression in CK2α, dnGSK3β and Cyclin D1 transgenic Mammary tissues was similar to that in ΔE3 β-catenin tissue. In support of transdifferentiation, expression of hard keratins specific for hair and nails was observed in pilar tumors. These results demonstrate that the activation of Wnt signaling components in Mammary Epithelium induces not only glandular tumors but also squamous differentiation, possibly by activating LEF-1, which is expressed in normal Mammary Epithelium.

D Joseph Jerry - One of the best experts on this subject based on the ideXlab platform.

Gertraud W Robinson - One of the best experts on this subject based on the ideXlab platform.

  • inactivation of stat5 in mouse Mammary Epithelium during pregnancy reveals distinct functions in cell proliferation survival and differentiation
    Molecular and Cellular Biology, 2004
    Co-Authors: Yongzhi Cui, Keiko Miyoshi, Gertraud W Robinson, Greg Riedlinger, Wei Tang, Chuxia Deng, Lothar Hennighausen
    Abstract:

    This study explored the functions of the signal transducers and activators of transcription 5a and 5b (referred to as Stat5 here) during different stages of mouse Mammary gland development by using conditional gene inactivation. Mammary gland morphogenesis includes cell specification, proliferation and differentiation during pregnancy, cell survival and maintenance of differentiation throughout lactation, and cell death during involution. Stat5 is activated by prolactin, and its presence is mandatory for the proliferation and differentiation of Mammary Epithelium during pregnancy. To address the question of whether Stat5 is also necessary for the maintenance and survival of the differentiated Epithelium, the two genes were deleted at different time points. The 110-kb Stat5 locus in the mouse was bracketed with loxP sites, and its deletion was accomplished by using two Cre-expressing transgenic lines. Loss of Stat5 prior to pregnancy prevented epithelial proliferation and differentiation. Deletion of Stat5 during pregnancy, after Mammary Epithelium had entered Stat5-mediated differentiation, resulted in premature cell death, indicating that at this stage epithelial cell proliferation, differentiation, and survival require Stat5.

  • Loss of connexin 26 in Mammary Epithelium during early but not during late pregnancy results in unscheduled apoptosis and impaired development.
    Developmental biology, 2004
    Co-Authors: Celine Bry, Keiko Miyoshi, Gertraud W Robinson, Karen Maass, Klaus Willecke, Thomas Ott, Lothar Hennighausen
    Abstract:

    Gap junctions are intercellular channels that are formed by the protein family of connexins (Cxs). In Mammary tissue, Cx26 and Cx32 are present in the secretory Epithelium and Cx43 is localized in the myoEpithelium. The expression of Cx26 and Cx32 is induced during pregnancy and lactation, respectively, thus suggesting unique roles for them in the functional development of the gland. The requirement for these connexins was explored using several strains of genetically altered mice: mice with an inactivated Cx32 gene, mice in which the Cx43 gene had been replaced with the Cx32 gene (Cx43KI32 mice) and mice in which the Cx26 gene was specifically ablated in Mammary Epithelium at different stages of development using Cre-loxP-based recombination. Normal Mammary development was obtained in Cx32-null mice and in Cx43KI32 Mammary tissue. In contrast, loss of Cx26 in Mammary Epithelium before puberty resulted in abrogated lobulo-alveolar development and increased cell death during pregnancy, which was accompanied by impaired lactation. Loss of Cx26 in Mammary Epithelium during the later part of pregnancy did not adversely interfere with functional Mammary development. These results demonstrate that the presence of Cx26 is critical during early stages but not during the end of pregnancy when the tissue has completed functional differentiation. Cx26 is considered a tumor suppressor gene and Cx26-null Mammary tissue was evaluated after five pregnancies. No hyperproliferation or hyperplasia was observed, suggesting that Cx26 does not function as a tumor suppressor.

  • selective removal of the selenocysteine trna ser sec gene trsp in mouse Mammary Epithelium
    Molecular and Cellular Biology, 2003
    Co-Authors: Easwari Kumaraswamy, Keiko Miyoshi, Fanta Morgan, Gertraud W Robinson, Bradley A Carlson, Dan Su, Shulin Wang, Eileen Southon, Lino Tessarollo, Vadim N Gladyshev
    Abstract:

    Mice homozygous for an allele encoding the selenocysteine (Sec) tRNA[Ser]Sec gene (Trsp) flanked by loxP sites were generated. Cre recombinase-dependent removal of Trsp in these mice was lethal to embryos. To investigate the role of Trsp in mouse Mammary Epithelium, we deleted this gene by using transgenic mice carrying the Cre recombinase gene under control of the mouse Mammary tumor virus (MMTV) long terminal repeat or the whey acidic protein promoter. While both promoters target Cre gene expression to Mammary Epithelium, MMTV-Cre is also expressed in spleen and skin. Sec tRNA[Ser]Sec amounts were reduced by more than 70% in Mammary tissue with either transgene, while in skin and spleen, levels were reduced only with MMTV-Cre. The selenoprotein population was selectively affected with MMTV-Cre in breast and skin but not in the control tissue, kidney. Moreover, within affected tissues, expression of specific selenoproteins was regulated differently and often in a contrasting manner, with levels of Sep15 and the glutathione peroxidases GPx1 and GPx4 being substantially reduced. Expression of the tumor suppressor genes BRCA1 and p53 was also altered in a contrasting manner in MMTV-Cre mice, suggesting greater susceptibility to cancer and/or increased cell apoptosis. Thus, the conditional Trsp knockout mouse allows tissue-specific manipulation of Sec tRNA and selenoprotein expression, suggesting that this approach will provide a useful tool for studying the role of selenoproteins in health.

  • Activation of different Wnt/β-catenin signaling components in Mammary Epithelium induces transdifferentiation and the formation of pilar tumors
    Oncogene, 2002
    Co-Authors: Keiko Miyoshi, Masahiro Nozawa, Andrea Rosner, Christopher Byrd, Fanta Morgan, Esther Landesman-bollag, David C Seldin, Emmett V Schmidt, Makato M Taketo, Gertraud W Robinson
    Abstract:

    The Wnt/β-catenin signaling pathway controls cell fate and neoplastic transformation. Expression of an endogenous stabilized β-catenin (ΔE3 β-catenin) in Mammary Epithelium leads to the transdifferentiation into epidermis- and pilar-like structures. Signaling molecules in the canonical Wnt pathway upstream from β-catenin induce glandular tumors but it is not clear whether they also cause squamous transdifferentiation. To address this question we have now investigated Mammary Epithelium from transgenic mice that express activating molecules of the Wnt pathway: Wnt10b, Int2/Fgf3, CK2α, ΔE3 β-catenin, Cyclin D1, and dominant negative (dn) GSK3β. Cytokeratin 5 (CK5), which is expressed in both Mammary myoEpithelium and epidermis, and the epidermis-specific CK1 and CK6 were used as differentiation markers. Extensive squamous metaplasias and widespread expression of CK1 and CK6 were observed in ΔE3 β-catenin transgenic Mammary tissue. Wnt10b and Int2 transgenes also induced squamous metaplasias, but expression of CK1 and CK6 was sporadic. While CK5 expression in Wnt10b transgenic tissue was still confined to the lining cell layer, its expression in Int2 transgenic tissue was completely disorganized. In contrast, cytokeratin expression in CK2α, dnGSK3β and Cyclin D1 transgenic Mammary tissues was similar to that in ΔE3 β-catenin tissue. In support of transdifferentiation, expression of hard keratins specific for hair and nails was observed in pilar tumors. These results demonstrate that the activation of Wnt signaling components in Mammary Epithelium induces not only glandular tumors but also squamous differentiation, possibly by activating LEF-1, which is expressed in normal Mammary Epithelium.

  • Rescue of Mammary Epithelium of Early Lethal Phenotypes by Embryonic Mammary Gland Transplantation as Exemplified with Insulin Receptor Null Mice
    Methods in Mammary Gland Biology and Breast Cancer Research, 2000
    Co-Authors: Gertraud W Robinson, Domenico Accili, Lothar Hennighausen
    Abstract:

    We describe a method to transplant embryonic Mammary anlagen into the Mammary fat pad of a virgin host whose endogenous Mammary Epithelium has been removed. The transplanted Epithelium grows into the fat pad and is exposed to a physiological hormonal milieu of puberty and pregnancy when the host is mated. This technique allows studies on the developmental potential of Mammary epithelia of mutants that result in lethality after embryonic day 13. Transplanted Mammary epithelial cells derived from insulin-receptor-deficient mice show reduced size of alveoli at lactation and reduced expression of milk protein genes. These results underscore the importance of insulin receptor signaling in Mammary epithelial development.

Ellen S Dickinson - One of the best experts on this subject based on the ideXlab platform.

  • Estrogen and progesterone regulate radiation-induced p53 activity in Mammary Epithelium through TGF-β-dependent pathways
    Oncogene, 2005
    Co-Authors: Klaus A Becker, Shaolei Lu, Ellen S Dickinson, Karen A Dunphy, Lesley Mathews, Sallie Smith Schneider, D Joseph Jerry
    Abstract:

    DNA damage normally induces p53 activity, but responses to ionizing radiation in the Mammary Epithelium vary among developmental stages. The following studies examined the hormones and growth factors that regulate radiation-responsiveness of p53 in mouse Mammary Epithelium. Immunoreactive p21/WAF1 and TUNEL staining were used as indicators of p53 activity following exposure to ionizing radiation. In ovariectomized mice, radiation-induced accumulation of p21/WAF1 was minimal in the Mammary epithelial cells (

  • Estrogen and progesterone regulate radiation-induced p53 activity in Mammary Epithelium through TGF-beta-dependent pathways.
    Oncogene, 2005
    Co-Authors: Klaus A Becker, Ellen S Dickinson, Karen A Dunphy, Lesley Mathews, Sallie Smith Schneider, D Joseph Jerry
    Abstract:

    DNA damage normally induces p53 activity, but responses to ionizing radiation in the Mammary Epithelium vary among developmental stages. The following studies examined the hormones and growth factors that regulate radiation-responsiveness of p53 in mouse Mammary Epithelium. Immunoreactive p21/WAF1 and TUNEL staining were used as indicators of p53 activity following exposure to ionizing radiation. In ovariectomized mice, radiation-induced accumulation of p21/WAF1 was minimal in the Mammary epithelial cells (

  • delayed involution of the Mammary Epithelium in balb c p53null mice
    Oncogene, 1998
    Co-Authors: D J Jerry, Ellen S Dickinson, Charlotte Kuperwasser, Sean R Downing, Jan Pinkas, S Marconi, Stephen P Naber
    Abstract:

    In mammals, weaning of neonates and subsequent milk stasis initiates removal of the secretory Epithelium of the Mammary gland by apoptosis. The p53 tumor suppressor gene is induced rapidly following weaning of neonates, but its role in the process of involution has not been defined. Therefore, experiments were performed to identify the cell types in which the p53 gene is expressed during involution and determine the consequences of its absence in BALB/c-p53null mice. Both p53 mRNA and protein were detected in the Mammary Epithelium within 48 h following weaning and resulted in an eightfold increase in levels of p21WAF1 mRNA. Induction of p21WAF1 mRNA was absent in BALB/c-p53null mice, and therefore, was shown to be p53-dependent. The BALB/c-p53null mice exhibited delayed involution of the Mammary Epithelium, as measured by 60% greater epithelial area compared to BALB/c-p53wt mice through 5 days post-weaning. The delay was transient with no differences being apparent at 7 days post-weaning. Expression of the stromal protease stromelysin-1 was unaffected by the absence of p53 suggesting that stromal responses were intact. These data demonstrate that p53 participates in the first stage of involution initiated by the Epithelium itself, but does not affect the second phase during which stromal proteases are induced.

Klaus A Becker - One of the best experts on this subject based on the ideXlab platform.

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