scholarly journals Mammary Epithelial Cells Are Not Able to Undergo Pregnancy-Dependent Differentiation in the Absence of the Helix-Loop-Helix Inhibitor Id2

2002 ◽  
Vol 16 (12) ◽  
pp. 2892-2901 ◽  
Author(s):  
Keiko Miyoshi ◽  
Barbara Meyer ◽  
Peter Gruss ◽  
Yongzhi Cui ◽  
Jean-Pierre Renou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Early Stage ◽  
Prolactin Receptor ◽  
Signal Transduction Pathway ◽  
Mammary Epithelium ◽  
Mammary Epithelial ◽  
Differentiation Markers ◽  
Helix Loop Helix ◽  
Alveolar Development

Abstract Mammary alveolar development during pregnancy is triggered by hormone signals. The prolactin receptor/Jak2/signal transducer and activator of transcription (Stat) 5 signal transduction pathway is the principal mediator of these cues and alveolar development is abrogated in its absence. The loss of the basic helix-loop-helix protein inhibitor of differentiation (Id)2 results in a similar defect. To investigate the role of Id2 in mammary epithelium, we performed structural and molecular analyses. Id2-null mammary epithelial cells were unable to form alveoli; the epithelial architecture was disorganized and dissimilar from early stages of alveologenesis in wild-type glands. The epithelial cells retained the ductal marker Na-K-Cl cotransporter (NKCC)1. Nuclear localization of Stat5a and down-regulation of NKCC1 was observed in some areas, indicating a limited response to pregnancy signals. The differentiation status of Id2-null tissue at term was further characterized with cDNA microarrays enriched in mammary specific sequences (mammochip). Some of the early differentiation markers for mammary epithelium were expressed in the Id2-null tissue, whereas genes that are expressed at later stages of pregnancy were not induced. From these results, we conclude that, in the absence of Id2, mammary epithelial development is arrested at an early stage of pregnancy.

Investigation of the role of microtubules in protein secretion from lactating mouse mammary epithelial cells

1992 ◽  
Vol 102 (2) ◽  
pp. 239-247 ◽  
Author(s):  
M.E. Rennison ◽  
S.E. Handel ◽  
C.J. Wilde ◽  
R.D. Burgoyne
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Protein Secretion ◽  
Secretory Pathway ◽  
Mammary Epithelial Cells ◽  
Early Stage ◽  
Major Effect ◽  
Vesicle Transport ◽  
Mammary Epithelial ◽  
Mammary Cells

Disruption of microtubules has been shown to reduce protein secretion from lactating mammary epithelial cells. To investigate the involvement of microtubules in the secretory pathway in these cells we have examined the effect of nocodazole on protein secretion from mammary epithelial cells derived from the lactating mouse. Mouse mammary cells have extensive microtubule networks and 85% of their tubulin was in a polymeric form. Treatment with 1 micrograms/ml nocodazole converted most of the tubulin into a soluble form. In a continuous labelling protocol it was found that nocodazole did not interfere with protein synthesis but over a 5 h period secretion was markedly inhibited. To determine whether the inhibition was at the level of early or late stages of the secretory pathway mammary cells were pulse-labelled for 1 h to label protein throughout the secretory pathway before nocodazole treatment. When secretion was subsequently assayed it was found to be slower and only partially inhibited. These findings suggest that the major effect of nocodazole is on an early stage of the secretory pathway and that microtubules normally facilitate vesicle transport to the plasma membrane. An involvement of microtubules in vesicle transport to the plasma membrane is consistent with an observed accumulation of casein vesicles in nocodazole-treated cells. Exocytosis stimulated by the calcium ionophore ionomycin was unaffected by nocodazole treatment. We conclude from these results that the major effect of nocodazole is at an early stage of the secretory pathway, one possible target being casein vesicle biogenesis in the trans-Golgi network.

scholarly journals Conditional Deletion of β-Catenin in Mammary Epithelial Cells of Ron Receptor, Mst1r, Overexpressing Mice Alters Mammary Tumorigenesis

Endocrinology ◽  
2012 ◽  
Vol 153 (6) ◽  
pp. 2735-2746 ◽  
Author(s):  
Purnima K. Wagh ◽  
Glendon M. Zinser ◽  
Jerilyn K. Gray ◽  
Archana Shrestha ◽  
Susan E. Waltz
Keyword(s):  
Epithelial Cells ◽  
Transgenic Mice ◽  
Target Genes ◽  
Mammary Epithelial Cells ◽  
Mammary Tumorigenesis ◽  
Mammary Epithelium ◽  
Mammary Tumors ◽  
Mammary Epithelial ◽  
Conditional Deletion ◽  
Ron Receptor

The Ron receptor tyrosine kinase (macrophage stimulating 1 receptor) is overexpressed in approximately 50% of human breast cancers. Transgenic mice overexpressing Ron in the mammary epithelium [mouse mammary tumor virus driven (MMTV)-Ron expressing mice] develop mammary tumors that exhibit up-regulation of β-catenin and β-catenin target genes. β-Catenin has been shown to be a mediator of mammary tumorigenesis in various breast cancer models, including downstream of Ron. However, the in vivo impact of a conditional loss of β-catenin downstream of Ron receptor overexpression on the onset, growth, turnover, and metastasis of mammary tumors has not been addressed. To determine the significance of β-catenin in the context of Ron overexpression, we conditionally deleted β-catenin in mammary epithelial cells of MMTV-Ron mice. Conditional deletion of β-catenin in the mammary epithelium, through the use of whey acidic protein (WAP)-Cre transgenic mice, significantly delayed the onset of mammary hyperplastic nodules, the presence of palpable mammary tumors, and ultimately decreased liver metastasis. β-Catenin loss in this model was also associated with decreased expression of cyclin D1. In total, these studies support an important role for β-catenin downstream of Ron receptor signaling during the development of mammary tumorigenesis.

miR-135a Targets and Regulates Prolactin Receptor Gene in Goat Mammary Epithelial Cells

2015 ◽  
Vol 34 (8) ◽  
pp. 534-540 ◽  
Author(s):  
Zhibin Ji ◽  
Fei Dong ◽  
Guizhi Wang ◽  
Lei Hou ◽  
Zhaohua Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Receptor Gene ◽  
Prolactin Receptor ◽  
Mammary Epithelial ◽  
Prolactin Receptor Gene ◽  
Goat Mammary Epithelial Cells

scholarly journals Matrix Metalloproteinase Stromelysin-1 Triggers a Cascade of Molecular Alterations That Leads to Stable Epithelial-to-Mesenchymal Conversion and a Premalignant Phenotype in Mammary Epithelial Cells

1997 ◽  
Vol 139 (7) ◽  
pp. 1861-1872 ◽  
Author(s):  
André Lochter ◽  
Sybille Galosy ◽  
John Muschler ◽  
Neal Freedman ◽  
Zena Werb ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Keratinocyte Growth Factor ◽  
Mammary Epithelium ◽  
Mammary Epithelial ◽  
Neoplastic Progression ◽  
Molecular Alterations ◽  
Epithelial Phenotype ◽  
Inappropriate Expression ◽  
E Cadherin

Matrix metalloproteinases (MMPs) regulate ductal morphogenesis, apoptosis, and neoplastic progression in mammary epithelial cells. To elucidate the direct effects of MMPs on mammary epithelium, we generated functionally normal cells expressing an inducible autoactivating stromelysin-1 (SL-1) transgene. Induction of SL-1 expression resulted in cleavage of E-cadherin, and triggered progressive phenotypic conversion characterized by disappearance of E-cadherin and catenins from cell–cell contacts, downregulation of cytokeratins, upregulation of vimentin, induction of keratinocyte growth factor expression and activation, and upregulation of endogenous MMPs. Cells expressing SL-1 were unable to undergo lactogenic differentiation and became invasive. Once initiated, this phenotypic conversion was essentially stable, and progressed even in the absence of continued SL-1 expression. These observations demonstrate that inappropriate expression of SL-1 initiates a cascade of events that may represent a coordinated program leading to loss of the differentiated epithelial phenotype and gain of some characteristics of tumor cells. Our data provide novel insights into how MMPs function in development and neoplastic conversion.

scholarly journals ErbB2/Neu-Induced, Cyclin D1-Dependent Transformation Is Accelerated in p27-Haploinsufficient Mammary Epithelial Cells but Impaired in p27-Null Cells

2002 ◽  
Vol 22 (7) ◽  
pp. 2204-2219 ◽  
Author(s):  
Rebecca S. Muraoka ◽  
Anne E. G. Lenferink ◽  
Brian Law ◽  
Elizabeth Hamilton ◽  
Dana M. Brantley ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cyclin D1 ◽  
Nuclear Localization ◽  
Nuclear Export ◽  
Mammary Epithelial Cells ◽  
Cell Transformation ◽  
Mammary Epithelium ◽  
Tumor Formation ◽  
Mammary Epithelial ◽  
Cdk4 Activity

ABSTRACT ErbB2/Neu destabilizes the cyclin-dependent kinase (Cdk) inhibitor p27 and increases expression of cyclin D1. Therefore, we studied the roles of p27 and cyclin D1 in ErbB2-mediated mammary epithelial cell transformation. Overexpression of ErbB2 or cyclin D1 in p27+/− primary murine mammary epithelial cells resulted in increased proliferation, cyclin D1 nuclear localization, and colony formation in soft agar compared to those in p27+/+ cells. In contrast, ErbB2- or cyclin D1-overexpressing p27−/− cells displayed reduced proliferation, anchorage-independent growth, Cdk4 activity, cyclin D1 expression, and cyclin D1 nuclear localization compared to wild-type cells. A cyclin D1 mutation in its nuclear export sequence (T286A) partially rescued nuclear localization of cyclin D1 in p27−/− cells but did not increase proliferation or Cdk4 kinase activity. Overexpression of E2F1, however, increased proliferation to the same degree in p27+/+ , p27+/− , and p27−/− cells. Mammary glands from MMTV (mouse mammary tumor virus)-neu/p27+/− mice exhibited alveolar hyperplasia, enhanced proliferation, decreased apoptosis, and accelerated tumor formation compared to MMTV-neu/p27+/+ glands. However, MMTV-neu/p27−/− glands showed decreased proliferation, cyclin D1 expression, and Cdk4 activity, as well as markedly prolonged tumor latency, compared to MMTV-neu/p27+/+ glands. These results suggest that p27+/− mammary epithelium may be more susceptible to oncogene-induced tumorigenesis, whereas p27-null glands, due to severely impaired cyclin D1/Cdk4 function, are more resistant to transformation.

scholarly journals The Intracellular Domain of ErbB4 Induces Differentiation of Mammary Epithelial Cells

2006 ◽  
Vol 17 (9) ◽  
pp. 4118-4129 ◽  
Author(s):  
Rebecca S. Muraoka-Cook ◽  
Melissa Sandahl ◽  
Carty Husted ◽  
Debra Hunter ◽  
Leah Miraglia ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Nuclear Localization ◽  
Transmembrane Domain ◽  
Mammary Epithelial Cells ◽  
Three Dimensional ◽  
Mammary Epithelial ◽  
Differentiation Markers ◽  
Intracellular Domain ◽  
Lumen Formation ◽  
Hc11 Cells

Differentiation of mammary epithelium in vivo requires signaling through prolactin- and ErbB4/HER4-dependent mechanisms; how these pathways intersect is unknown. We show herein that HC11 mouse mammary cells undergo ErbB4-dependent lactational differentiation. Prolactin and the ErbB4 ligand HB-EGF each induced STAT5A activation, expression of lactogenic differentiation markers, and lumen formation in three-dimensional Matrigel cultures in HC11 cells. ErbB4 undergoes ligand-dependent transmembrane domain cleavage at Val-675, releasing a soluble 80-kDa intracellular domain (s80HER4) that localizes to nuclei; the physiological relevance of s80HER4 is unknown. A HER4V675A mutant abolishing transmembrane cleavage impaired STAT5A activity, lactogenic gene expression, and lumen formation. Kinase-dead HER4KD was neither cleaved nor able to induce differentiation of HC11 cells. Without treating HC11 cells with prolactin or HB-EGF, s80HER4 (expressed from a cDNA construct) localized to the nucleus, activated STAT5A, and induced three-dimensional lumen formation. Nuclear localization of exogenous s80HER4 required intact kinase activity of s80HER4, as did activation of STAT5A. In contrast, nuclear localization of s80HER4 and STAT5A activation did not require the 16-amino acid region of the ErbB4 intracellular domain specific to the Cyt-1 isoform of ErbB4, and absent in the Cyt-2 isoform. These results suggest that s80HER4 formation contributes to ErbB4-dependent differentiation of mammary epithelial cells.

Developmental role of the SNF1-related kinase Hunk in pregnancy-induced changes in the mammary gland

Development ◽  
2000 ◽  
Vol 127 (20) ◽  
pp. 4493-4509
Author(s):  
H.P. Gardner ◽  
G.K. Belka ◽  
G.B. Wertheim ◽  
J.L. Hartman ◽  
S.I. Ha ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelium ◽  
Ovarian Hormones ◽  
Mammary Development ◽  
Mammary Epithelial ◽  
Serine Threonine Kinase ◽  
Proliferation And Differentiation ◽  
Induced Changes

The steroid hormones 17 beta-estradiol and progesterone play a central role in the pathogenesis of breast cancer and regulate key phases of mammary gland development. This suggests that developmental regulatory molecules whose activity is influenced by ovarian hormones may also contribute to mammary carcinogenesis. In a screen designed to identify protein kinases expressed in the mammary gland, we previously identified a novel SNF1-related serine/threonine kinase, Hunk (hormonally upregulated Neu-associated kinase). During postnatal mammary development, Hunk mRNA expression is restricted to a subset of mammary epithelial cells and is temporally regulated with highest levels of expression occurring during early pregnancy. In addition, treatment of mice with 17 beta-estradiol and progesterone results in the rapid and synergistic upregulation of Hunk expression in a subset of mammary epithelial cells, suggesting that the expression of this kinase may be regulated by ovarian hormones. Consistent with the tightly regulated pattern of Hunk expression during pregnancy, mammary glands from transgenic mice engineered to misexpress Hunk in the mammary epithelium manifest temporally distinct defects in epithelial proliferation and differentiation during pregnancy, and fail to undergo normal lobuloalveolar development. Together, these observations suggest that Hunk may contribute to changes in the mammary gland that occur during pregnancy in response to ovarian hormones.

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