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Werner Boecker - One of the best experts on this subject based on the ideXlab platform.

  • spatially correlated phenotyping reveals k5 positive luminal progenitor cells and p63 k5 14 positive stem cell like cells in human Breast Epithelium
    Laboratory Investigation, 2018
    Co-Authors: Werner Boecker, Göran Stenman, Udo Schumacher, Thomas Loening, Laura Van Horn, Christine Sturken, Lukas Liesenfeld, Eberhard Korsching, Doreen Glaser, Katharina Tiemann
    Abstract:

    Understanding the mechanisms regulating human mammary Epithelium requires knowledge of the cellular constituents of this tissue. Different and partially contradictory definitions and concepts describing the cellular hierarchy of mammary Epithelium have been proposed, including our studies of keratins K5 and/or K14 as markers of progenitor cells. Furthermore, we and others have suggested that the p53 homolog p63 is a marker of human Breast epithelial stem cells. In this investigation, we expand our previous studies by testing whether immunohistochemical staining with monospecific anti-keratin antibodies in combination with an antibody against the stem cell marker p63 might help refine the different morphologic phenotypes in normal Breast Epithelium. We used in situ multilabel staining for p63, different keratins, the myoepithelial marker smooth muscle actin (SMA), the estrogen receptor (ER), and Ki67 to dissect and quantify the cellular components of 16 normal pre- and postmenopausal human Breast epithelial tissue samples at the single-cell level. Importantly, we confirm the existence of K5+ only cells and suggest that they, in contrast to the current view, are key luminal precursor cells from which K8/18+ progeny cells evolve. These cells are further modified by the expression of ER and Ki67. We have also identified a population of p63+K5+ cells that are only found in nipple ducts. Based on our findings, we propose a new concept of the cellular hierarchy of human Breast Epithelium, including K5 luminal lineage progenitors throughout the ductal-lobular axis and p63+K5+ progenitors confined to the nipple ducts. The authors propose a model of the hierarchical organization of Breast ducts and lobules. They describe luminal progenitors from which glandular progeny cells evolve, and demonstrate the presence of a small subpopulation of bipotent progenitors confined to the nipple ducts. Moreover, they show that estrogen receptor expression is associated with differentiated glandular cells and is rarely observed in progenitors. These results may provide new important insights into the definition and regulation of stem/progenitor cells in normal and diseased Breast tissues.

  • Multicolor immunofluorescence reveals that p63- and/or K5-positive progenitor cells contribute to normal Breast Epithelium and usual ductal hyperplasia but not to low-grade intraepithelial neoplasia of the Breast
    Virchows Archiv, 2017
    Co-Authors: Werner Boecker, Göran Stenman, Tina Schroeder, Udo Schumacher, Thomas Loening, Lisa Stahnke, Catharina Löhnert, Robert Michael Siering, Arthur Kuper, Vera Samoilova
    Abstract:

    We contend that knowledge about the cellular composition of normal Breast Epithelium is a prerequisite for understanding proliferative Breast disease. Against this background, we used multicolor immunofluorescence to study normal Breast Epithelium and two types of intraepithelial proliferative Breast lesion for expression of the p63, basal keratin K5, glandular keratin K8/18, SMA, ER-alpha, and Ki67. We studied eight normal Breast Epithelium samples, 12 cases of usual ductal hyperplasia, and 33 cases of low-grade intraepithelial neoplasia (9 flat epithelial atypia, 14 low-grade ductal carcinoma in situ and 10 cases of lobular neoplasia). Usual ductal hyperplasia showed striking similarity to normal luminal Breast Epithelium including p63+ and/or K5+ luminal progenitor cells and the full spectrum of luminal progeny cells. In normal Breast Epithelium and usual ductal hyperplasia, expression of ER-alpha was associated with lack of expression of the proliferation antigen Ki67. In contrast, we found in both types of low-grade intraepithelial neoplasia robust expression of keratin K8/18 and a positive association between ER-alpha and Ki67 expression. However, these lesions were consistently negative for p63 and/or K5. Our observational study supports the view that usual ductal hyperplasia and low-grade intraepithelial neoplasia are different entities rather than part of a spectrum of the same disease. We propose a new operational model of cell differentiation that may serve to better understand correlations between normal Breast Epithelium and proliferative Breast diseases. From our data we conclude that p63+ and/or K5+ progenitor cells contribute to maintenance of normal Epithelium and usual ductal hyperplasia, but not to low-grade intraepithelial neoplasia of the Breast.

  • multicolor immunofluorescence reveals that p63 and or k5 positive progenitor cells contribute to normal Breast Epithelium and usual ductal hyperplasia but not to low grade intraepithelial neoplasia of the Breast
    Virchows Archiv, 2017
    Co-Authors: Werner Boecker, Göran Stenman, Tina Schroeder, Udo Schumacher, Thomas Loening, Lisa Stahnke, Catharina Löhnert, Robert Michael Siering, Arthur Kuper, Vera Samoilova
    Abstract:

    We contend that knowledge about the cellular composition of normal Breast Epithelium is a prerequisite for understanding proliferative Breast disease. Against this background, we used multicolor immunofluorescence to study normal Breast Epithelium and two types of intraepithelial proliferative Breast lesion for expression of the p63, basal keratin K5, glandular keratin K8/18, SMA, ER-alpha, and Ki67. We studied eight normal Breast Epithelium samples, 12 cases of usual ductal hyperplasia, and 33 cases of low-grade intraepithelial neoplasia (9 flat epithelial atypia, 14 low-grade ductal carcinoma in situ and 10 cases of lobular neoplasia). Usual ductal hyperplasia showed striking similarity to normal luminal Breast Epithelium including p63+ and/or K5+ luminal progenitor cells and the full spectrum of luminal progeny cells. In normal Breast Epithelium and usual ductal hyperplasia, expression of ER-alpha was associated with lack of expression of the proliferation antigen Ki67. In contrast, we found in both types of low-grade intraepithelial neoplasia robust expression of keratin K8/18 and a positive association between ER-alpha and Ki67 expression. However, these lesions were consistently negative for p63 and/or K5. Our observational study supports the view that usual ductal hyperplasia and low-grade intraepithelial neoplasia are different entities rather than part of a spectrum of the same disease. We propose a new operational model of cell differentiation that may serve to better understand correlations between normal Breast Epithelium and proliferative Breast diseases. From our data we conclude that p63+ and/or K5+ progenitor cells contribute to maintenance of normal Epithelium and usual ductal hyperplasia, but not to low-grade intraepithelial neoplasia of the Breast.

  • differentiation and histogenesis of syringomatous tumour of the nipple and low grade adenosquamous carcinoma evidence for a common origin
    Histopathology, 2014
    Co-Authors: Werner Boecker, Göran Stenman, Thomas Loening, Mattias K Andersson, Hanspeter Sinn, Peter Barth, Felix Oberhellmann, Inge Bos, Tobias Berg, Zlatko Marusic
    Abstract:

    Aims Syringomatous tumour of the nipple and low-grade adenosquamous carcinoma (LGAdSC) of the Breast are regarded as distinct entities. To clarify the nature of these two lesions, we compared the expression of different lineage/differentiation markers in 12 syringomatous tumours of the nipple, nine LGAdSCs, and normal Breast Epithelium. Methods and results Using triple immunofluorescence labelling and quantitative RT-PCR for keratins, p63, and smooth muscle actin, we demonstrated that syringomatous tumour and LGAdSC contain p63+/K5/14+ tumour cells, K10+ squamous cells, and K8/18+ glandular cells, with intermediary cells being found in both lineages. Identical p63+/K5/14+ cells were also found in the normal Breast duct Epithelium. Conclusions Our data provide evidence that syringomatous tumour of the nipple and LGAdSC are identical or nearly identical lesions. They contain p63+/K5/14+ cells as the key cells from which the K10+ squamous lineage and the K8/18+ glandular lineage arise. On the basis of our findings in normal Breast tissue and associated benign lesions, we suggest that p63+/K5/14+ cells of the normal Breast duct Epithelium or early related cells might play a key role in the neoplastic transformation of both syringomatous tumour and LGAdSC. We propose that the differentiation patterns found in both lesions reflect the early ontogenetic stages of the normal Breast Epithelium.

  • evidence of progenitor cells of glandular and myoepithelial cell lineages in the human adult female Breast Epithelium a new progenitor adult stem cell concept
    Cell Proliferation, 2003
    Co-Authors: Werner Boecker, Horst Buerger
    Abstract:

    Although experimental data clearly confirm the existence of self-renewing mammary stem cells, the characteristics of such progenitor cells have never been satisfactorily defined. Using a double immunofluorescence technique for simultaneous detection of the basal cytokeratin 5, the glandular cytokeratins 8/18 and the myoepithelial differentiation marker smooth muscle actin (SMA), we were able to demonstrate the presence of Ck5 + cells in human adult Breast Epithelium. These cells have the potential to differentiate to either glandular (CK8/18 + ) or myoepithelial cells (SMA + ) through intermediary cells (CK5 + and CK8/18 + or SMA + ). We therefore proceeded on the assumption that the CK5 + cells are phenotypically and behaviourally progenitor (committed adult stem) cells of human Breast Epithelium. Furthermore, we furnish evidence that most of these progenitor cells are located in the luminal Epithelium of the ductal lobular tree. Based on data obtained in extensive analyses of proliferative Breast disease lesions, we have come to regard usual ductal hyperplasia as a progenitor cell-derived lesion, whereas most Breast cancers seem to evolve from differentiated glandular cells. Double immunofluorescence experiments provide a new tool to characterize phenotypically progenitor (adult stem) cells and their progenies. This model has been shown to be of great value for a better understanding not only of normal tissue regeneration but also of proliferative Breast disease. Furthermore, this model provides a new tool for unravelling further the regulatory mechanisms that govern normal and pathological cell growth.

Liam J Murray - One of the best experts on this subject based on the ideXlab platform.

Dana Bazzoun - One of the best experts on this subject based on the ideXlab platform.

  • connexin 43 maintains tissue polarity and regulates mitotic spindle orientation in the Breast Epithelium
    Journal of Cell Science, 2019
    Co-Authors: Dana Bazzoun, Sabreen Fostok, Hibret A Adissu, Lei Wang, A K Urazaev, Iliana Tenvooren, Shirisha Chittiboyina, Jennifer Sturgis, Kurt B Hodges, Gurushankar Chandramouly
    Abstract:

    ABSTRACT Cell–cell communication is essential for tissue homeostasis, but its contribution to disease prevention remains to be understood. We demonstrate the involvement of connexin 43 (Cx43, also known as GJA1) and related gap junction in epithelial homeostasis, illustrated by polarity-mediated cell cycle entry and mitotic spindle orientation (MSO). Cx43 localization is restricted to the apicolateral membrane of phenotypically normal Breast luminal epithelial cells in 3D culture and in vivo . Chemically induced blockade of gap junction intercellular communication (GJIC), as well as the absence of Cx43, disrupt the apicolateral distribution of polarity determinant tight junction marker ZO-1 (also known as TJP1) and lead to random MSO and cell multilayering. Induced expression of Cx43 in cells that normally lack this protein reestablishes polarity and proper MSO in 3D culture. Cx43-directed MSO implicates PI3K–aPKC signaling, and Cx43 co-precipitates with signaling node proteins β-catenin (CTNNB1) and ZO-2 (also known as TJP2) in the polarized Epithelium. The distribution of Cx43 is altered by pro-inflammatory Breast cancer risk factors such as leptin and high-fat diet, as shown in cell culture and on tissue biopsy sections. The control of polarity-mediated quiescence and MSO may contribute to the tumor-suppressive role of Cx43.

  • connexin 43 loss triggers cell cycle entry and invasion in non neoplastic Breast Epithelium a role for noncanonical wnt signaling
    Cancers, 2019
    Co-Authors: Sabreen Fostok, Dana Bazzoun, Mirvat Elsibai, Sophie A Lelievre, Rabih Talhouk
    Abstract:

    (1) Background: The expression of connexin 43 (Cx43) is disrupted in Breast cancer, and re-expression of this protein in human Breast cancer cell lines leads to decreased proliferation and invasiveness, suggesting a tumor suppressive role. This study aims to investigate the role of Cx43 in proliferation and invasion starting from non-neoplastic Breast Epithelium. (2) Methods: Nontumorigenic human mammary epithelial HMT-3522 S1 cells and Cx43 shRNA-transfected counterparts were cultured under 2-dimensional (2-D) and 3-D conditions. (3) Results: Silencing Cx43 induced mislocalization of β-catenin and Scrib from apicolateral membrane domains in glandular structures or acini formed in 3-D culture, suggesting the loss of apical polarity. Cell cycle entry and proliferation were enhanced, concomitantly with c-Myc and cyclin D1 upregulation, while no detectable activation of Wnt/β-catenin signaling was observed. Motility and invasion were also triggered and were associated with altered acinar morphology and activation of ERK1/2 and Rho GTPase signaling, which acts downstream of the noncanonical Wnt pathway. The invasion of Cx43-shRNA S1 cells was observed only under permissive stiffness of the extracellular matrix (ECM). (4) Conclusion: Our results suggest that Cx43 controls proliferation and invasion in the normal mammary Epithelium in part by regulating noncanonical Wnt signaling.

  • Connexin 43 Loss Triggers Cell Cycle Entry and Invasion in Non-Neoplastic Breast Epithelium: A Role for Noncanonical Wnt Signaling
    MDPI AG, 2019
    Co-Authors: Sabreen Fostok, Mirvat El-sibai, Dana Bazzoun, Sophie Lelièvre, Rabih Talhouk
    Abstract:

    (1) Background: The expression of connexin 43 (Cx43) is disrupted in Breast cancer, and re-expression of this protein in human Breast cancer cell lines leads to decreased proliferation and invasiveness, suggesting a tumor suppressive role. This study aims to investigate the role of Cx43 in proliferation and invasion starting from non-neoplastic Breast Epithelium. (2) Methods: Nontumorigenic human mammary epithelial HMT-3522 S1 cells and Cx43 shRNA-transfected counterparts were cultured under 2-dimensional (2-D) and 3-D conditions. (3) Results: Silencing Cx43 induced mislocalization of β-catenin and Scrib from apicolateral membrane domains in glandular structures or acini formed in 3-D culture, suggesting the loss of apical polarity. Cell cycle entry and proliferation were enhanced, concomitantly with c-Myc and cyclin D1 upregulation, while no detectable activation of Wnt/β-catenin signaling was observed. Motility and invasion were also triggered and were associated with altered acinar morphology and activation of ERK1/2 and Rho GTPase signaling, which acts downstream of the noncanonical Wnt pathway. The invasion of Cx43-shRNA S1 cells was observed only under permissive stiffness of the extracellular matrix (ECM). (4) Conclusion: Our results suggest that Cx43 controls proliferation and invasion in the normal mammary Epithelium in part by regulating noncanonical Wnt signaling

J A Glover - One of the best experts on this subject based on the ideXlab platform.

Vera Samoilova - One of the best experts on this subject based on the ideXlab platform.

  • Multicolor immunofluorescence reveals that p63- and/or K5-positive progenitor cells contribute to normal Breast Epithelium and usual ductal hyperplasia but not to low-grade intraepithelial neoplasia of the Breast
    Virchows Archiv, 2017
    Co-Authors: Werner Boecker, Göran Stenman, Tina Schroeder, Udo Schumacher, Thomas Loening, Lisa Stahnke, Catharina Löhnert, Robert Michael Siering, Arthur Kuper, Vera Samoilova
    Abstract:

    We contend that knowledge about the cellular composition of normal Breast Epithelium is a prerequisite for understanding proliferative Breast disease. Against this background, we used multicolor immunofluorescence to study normal Breast Epithelium and two types of intraepithelial proliferative Breast lesion for expression of the p63, basal keratin K5, glandular keratin K8/18, SMA, ER-alpha, and Ki67. We studied eight normal Breast Epithelium samples, 12 cases of usual ductal hyperplasia, and 33 cases of low-grade intraepithelial neoplasia (9 flat epithelial atypia, 14 low-grade ductal carcinoma in situ and 10 cases of lobular neoplasia). Usual ductal hyperplasia showed striking similarity to normal luminal Breast Epithelium including p63+ and/or K5+ luminal progenitor cells and the full spectrum of luminal progeny cells. In normal Breast Epithelium and usual ductal hyperplasia, expression of ER-alpha was associated with lack of expression of the proliferation antigen Ki67. In contrast, we found in both types of low-grade intraepithelial neoplasia robust expression of keratin K8/18 and a positive association between ER-alpha and Ki67 expression. However, these lesions were consistently negative for p63 and/or K5. Our observational study supports the view that usual ductal hyperplasia and low-grade intraepithelial neoplasia are different entities rather than part of a spectrum of the same disease. We propose a new operational model of cell differentiation that may serve to better understand correlations between normal Breast Epithelium and proliferative Breast diseases. From our data we conclude that p63+ and/or K5+ progenitor cells contribute to maintenance of normal Epithelium and usual ductal hyperplasia, but not to low-grade intraepithelial neoplasia of the Breast.

  • multicolor immunofluorescence reveals that p63 and or k5 positive progenitor cells contribute to normal Breast Epithelium and usual ductal hyperplasia but not to low grade intraepithelial neoplasia of the Breast
    Virchows Archiv, 2017
    Co-Authors: Werner Boecker, Göran Stenman, Tina Schroeder, Udo Schumacher, Thomas Loening, Lisa Stahnke, Catharina Löhnert, Robert Michael Siering, Arthur Kuper, Vera Samoilova
    Abstract:

    We contend that knowledge about the cellular composition of normal Breast Epithelium is a prerequisite for understanding proliferative Breast disease. Against this background, we used multicolor immunofluorescence to study normal Breast Epithelium and two types of intraepithelial proliferative Breast lesion for expression of the p63, basal keratin K5, glandular keratin K8/18, SMA, ER-alpha, and Ki67. We studied eight normal Breast Epithelium samples, 12 cases of usual ductal hyperplasia, and 33 cases of low-grade intraepithelial neoplasia (9 flat epithelial atypia, 14 low-grade ductal carcinoma in situ and 10 cases of lobular neoplasia). Usual ductal hyperplasia showed striking similarity to normal luminal Breast Epithelium including p63+ and/or K5+ luminal progenitor cells and the full spectrum of luminal progeny cells. In normal Breast Epithelium and usual ductal hyperplasia, expression of ER-alpha was associated with lack of expression of the proliferation antigen Ki67. In contrast, we found in both types of low-grade intraepithelial neoplasia robust expression of keratin K8/18 and a positive association between ER-alpha and Ki67 expression. However, these lesions were consistently negative for p63 and/or K5. Our observational study supports the view that usual ductal hyperplasia and low-grade intraepithelial neoplasia are different entities rather than part of a spectrum of the same disease. We propose a new operational model of cell differentiation that may serve to better understand correlations between normal Breast Epithelium and proliferative Breast diseases. From our data we conclude that p63+ and/or K5+ progenitor cells contribute to maintenance of normal Epithelium and usual ductal hyperplasia, but not to low-grade intraepithelial neoplasia of the Breast.