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Search Results: 1 - 10 of 297734 matches for " Connie J. Eaves "
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The future of mammary stem cell biology: the power of in vivo transplants
Geoffrey J Lindeman, Jane E Visvader, Matthew J Smalley, Connie J Eaves
Breast Cancer Research , 2008, DOI: 10.1186/bcr1986
Abstract: Smith and Medina [1] suggest that a conflict may exist in the consistency of CD49f, CD29 and CD24 as positive mouse MaSC markers. However, we find the results reported thus far to be in full agreement with one another. The CD49fhi/CD24med population described by Stingl and coworkers [6] is identical to the CD29hi/CD24+ population described by Shackleton and colleagues [4] and to the CD49fhi/CD24lo/Sca-1-population reported by Sleeman and coworkers [5]. Specifically, there is considerable overlap (> 85%) between the fraction of CD24+ cells that are CD49fhi and CD29hi, suggesting that α6 and β1 integrin (CD49f and CD29, respectively) are co-expressed in the basal stem cell-enriched population (unpublished data). Although the MaSC-enriched population is CD24+, the level of expression is clearly lower than in cells with luminal features, including luminal progenitors [5,6]. Different levels of fluorescence are obtained with different anti-CD24 reagents and staining protocols, and this has led to differential reporting of MaSCs as CD24+, CD24mod, or CD24lo [8]. The resultant confusion is unfortunate and underscores the need for improved standardization in phenotyping procedures and nomenclature.There is also consistency in the reported phenotypes of luminal progenitors and their more mature progeny. The latter are widely recognized to be CD24+/hi/CD29lo/CD61-/prominin-1+/Sca-1+, whereas the luminal progenitors are CD24+/hi/CD29lo/CD61+/prominin-1-. The CD24hi/prominin-1-/Sca-1- population described by Sleeman and coworkers [8] contains within it the CD29lo/CD24+/CD61+population isolated by Asselin-Labat and coworkers [9] (Smalley MJ, unpublished data). This accounts for our similar observations of oestrogen receptor-α expression being largely confined to the more mature CD24+/hi/CD61-/prominin-1+/Sca-1+ luminal cells (although a potentially important finding is that a small fraction of luminal progenitor cells also express ER-α) [8-10].Smith and Medina [1] rightly highli
Meta-Analysis of Differentiating Mouse Embryonic Stem Cell Gene Expression Kinetics Reveals Early Change of a Small Gene Set
Clive H Glover,Michael Marin,Connie J Eaves,Cheryl D Helgason,James M Piret,Jennifer Bryan
PLOS Computational Biology , 2006, DOI: 10.1371/journal.pcbi.0020158
Abstract: Stem cell differentiation involves critical changes in gene expression. Identification of these should provide endpoints useful for optimizing stem cell propagation as well as potential clues about mechanisms governing stem cell maintenance. Here we describe the results of a new meta-analysis methodology applied to multiple gene expression datasets from three mouse embryonic stem cell (ESC) lines obtained at specific time points during the course of their differentiation into various lineages. We developed methods to identify genes with expression changes that correlated with the altered frequency of functionally defined, undifferentiated ESC in culture. In each dataset, we computed a novel statistical confidence measure for every gene which captured the certainty that a particular gene exhibited an expression pattern of interest within that dataset. This permitted a joint analysis of the datasets, despite the different experimental designs. Using a ranking scheme that favored genes exhibiting patterns of interest, we focused on the top 88 genes whose expression was consistently changed when ESC were induced to differentiate. Seven of these (103728_at, 8430410A17Rik, Klf2, Nr0b1, Sox2, Tcl1, and Zfp42) showed a rapid decrease in expression concurrent with a decrease in frequency of undifferentiated cells and remained predictive when evaluated in additional maintenance and differentiating protocols. Through a novel meta-analysis, this study identifies a small set of genes whose expression is useful for identifying changes in stem cell frequencies in cultures of mouse ESC. The methods and findings have broader applicability to understanding the regulation of self-renewal of other stem cell types.
Human Milk Protein Production in Xenografts of Genetically Engineered Bovine Mammary Epithelial Stem Cells
Eugenio Martignani,Peter Eirew,Paolo Accornero,Connie J. Eaves,Mario Baratta
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013372
Abstract: In the bovine species milk production is well known to correlate with mammary tissue mass. However, most advances in optimizing milk production relied on improvements of breeding and husbandry practices. A better understanding of the cells that generate bovine mammary tissue could facilitate important advances in milk production and have global economic impact. With this possibility in mind, we show that a mammary stem cell population can be functionally identified and isolated from the bovine mammary gland. We also demonstrate that this stem cell population may be a promising target for manipulating the composition of cow's milk using gene transfer.
Expression of the leukemic prognostic marker CD7 is linked to epigenetic modifications in chronic myeloid leukemia
Sally L Rogers, Yun Zhao, Xiaoyan Jiang, Connie J Eaves, Dixie L Mager, Arefeh Rouhi
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-41
Abstract: To address this question, we compared the level of their expression with the DNA methylation and histone acetylation status of 5' sequences of both genes in leukemic cell lines and primitive (lin-CD34+) leukemic cells from chronic phase CML patients. DNA methylation of the ELA2 gene promoter did not correlate with its expression pattern in lin-CD34+ cells from chronic phase CML patient samples even though there was clear differential DNA methylation of this locus in ELA2-expressing and non-expressing cell lines. In contrast, we found a strong relation between CD7 expression and transcription-permissive chromatin modifications, both at the level of DNA methylation and histone acetylation with evidence of hypomethylation of the CD7 promoter region in the lin-CD34+ cells from CML patients with high CD7 expression.These findings indicate a link between epigenetic modifications and CD7 expression in primitive CML cells.A feature of chronic myeloid leukaemia (CML) is the Philadelphia chromosome (Ph). This abnormal chromosome results from a reciprocal translocation between chromosome 9 and 22 that gives rise to the BCR-ABL fusion gene that is now the accepted defining hallmark of the disease [1-3]. CML is typically diagnosed in an initial chronic phase (CP) which is characterized by the formation of a multi-lineage clone of Ph+/BCR-ABL+ leukemic cells that typically dominates the entire hematopoietic system by the time of diagnosis. This clone includes a selectively enlarged compartment of myeloid progenitors that produce an elevated number of normally differentiated granulocytes [4]. Targeted therapy of CML with imatinib mesylate (IM) or other inhibitors of the BCR-ABL oncoprotein is the current therapy of choice for patients with CP disease, although IM does not always produce durable remissions [5,6]. The most common cause of a poor response outcome is the appearance of IM-resistant cells. This resistance might be BCR-ABL-dependent, such as mutations in the kinase domai
Molecular Decoy to the Y-Box Binding Protein-1 Suppresses the Growth of Breast and Prostate Cancer Cells whilst Sparing Normal Cell Viability
Jennifer H. Law,Yvonne Li,Karen To,Michelle Wang,Arezoo Astanehe,Karen Lambie,Jaspreet Dhillon,Steven J. M. Jones,Martin E. Gleave,Connie J. Eaves,Sandra E. Dunn
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012661
Abstract: The Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was highly phosphorylated by the serine/threonine p90 S6 kinases RSK-1 and RSK-2, and to a lesser degree PKCα and AKT. Herein, we sought to develop this decoy cell permeable peptide (CPP) as a cancer therapeutic. This 9-mer was designed as an interference peptide that would prevent endogenous YB-1S102 phosphorylation based on molecular docking. In cancer cells, the CPP blocked P-YB-1S102 and down-regulated both HER-2 and EGFR transcript level and protein expression. Further, the CPP prevented YB-1 from binding to the EGFR promoter in a gel shift assay. Notably, the growth of breast (SUM149, MDA-MB-453, AU565) and prostate (PC3, LNCap) cancer cells was inhibited by ~90% with the CPP. Further, treatment with this peptide enhanced sensitivity and overcame resistance to trastuzumab in cells expressing amplified HER-2. By contrast, the CPP had no inhibitory effect on the growth of normal immortalized breast epithelial (184htert) cells, primary breast epithelial cells, nor did it inhibit differentiation of hematopoietic progenitors. These data collectively suggest that the CPP is a novel approach to suppressing the growth of cancer cells while sparing normal cells and thereby establishes a proof-of-concept that blocking YB-1 activation is a new course of cancer therapeutics.
The BRG1 Chromatin Remodeler Protects Against Ovarian Cysts, Uterine Tumors, and Mammary Tumors in a Lineage-Specific Manner
Daniel W. Serber, Allison Rogala, Maisam Makarem, Gary B. Rosson, Karl Simin, Virginia Godfrey, Terry Van Dyke, Connie J. Eaves, Scott J. Bultman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031346
Abstract: The BRG1 catalytic subunit of SWI/SNF-related complexes is required for mammalian development as exemplified by the early embryonic lethality of Brg1 null homozygous mice. BRG1 is also a tumor suppressor and, in mice, 10% of heterozygous (Brg1null/+) females develop mammary tumors. We now demonstrate that BRG1 mRNA and protein are expressed in both the luminal and basal cells of the mammary gland, raising the question of which lineage requires BRG1 to promote mammary homeostasis and prevent oncogenic transformation. To investigate this question, we utilized Wap-Cre to mutate both Brg1 floxed alleles in the luminal cells of the mammary epithelium of pregnant mice where WAP is exclusively expressed within the mammary gland. Interestingly, we found that Brg1Wap-Cre conditional homozygotes lactated normally and did not develop mammary tumors even when they were maintained on a Brm-deficient background. However, Brg1Wap-Cre mutants did develop ovarian cysts and uterine tumors. Analysis of these latter tissues showed that both, like the mammary gland, contain cells that normally express Brg1 and Wap. Thus, tumor formation in Brg1 mutant mice appears to be confined to particular cell types that require BRG1 and also express Wap. Our results now show that such cells exist both in the ovary and the uterus but not in either the luminal or the basal compartments of the mammary gland. Taken together, these findings indicate that SWI/SNF-related complexes are dispensable in the luminal cells of the mammary gland and therefore argue against the notion that SWI/SNF-related complexes are essential for cell survival. These findings also suggest that the tumor-suppressor activity of BRG1 is restricted to the basal cells of the mammary gland and demonstrate that this function extends to other female reproductive organs, consistent with recent observations of recurrent ARID1A/BAF250a mutations in human ovarian and endometrial tumors.
Developmental Changes in the in Vitro Activated Regenerative Activity of Primitive Mammary Epithelial Cells
Maisam Makarem,Nagarajan Kannan,Long V. Nguyen,David J. H. F. Knapp,Sneha Balani,Michael D. Prater,John Stingl,Afshin Raouf,Oksana Nemirovsky,Peter Eirew,Connie J. Eaves
PLOS Biology , 2013, DOI: 10.1371/journal.pbio.1001630
Abstract: Many normal adult tissues contain rare stem cells with extensive self-maintaining regenerative potential. During development, the stem cells of the hematopoietic and neural systems undergo intrinsically specified changes in their self-renewal potential. In the mouse, mammary stem cells with transplantable regenerative activity are first detectable a few days before birth. They share some phenotypic properties with their adult counterparts but are enriched in a subpopulation that displays a distinct gene expression profile. Here we show that fetal mammary epithelial cells have a greater direct and inducible growth potential than their adult counterparts. The latter feature is revealed in a novel culture system that enables large numbers of in vitro clonogenic progenitors as well as mammary stem cells with serially transplantable activity to be produced within 7 days from single fetal or adult input cells. We further show that these responses are highly dependent on novel factors produced by fibroblasts. These findings provide new avenues for elucidating mechanisms that regulate normal mammary epithelial stem cell properties at the single-cell level, how these change during development, and how their perturbation may contribute to transformation.
Growth Arrest Specific 2 Is Up-Regulated in Chronic Myeloid Leukemia Cells and Required for Their Growth
Haixia Zhou, Yue Ge, Lili Sun, Wenjuan Ma, Jie Wu, Xiuyan Zhang, Xiaohui Hu, Connie J. Eaves, Depei Wu, Yun Zhao
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086195
Abstract: Although the generation of BCR-ABL is the molecular hallmark of chronic myeloid leukemia (CML), the comprehensive molecular mechanisms of the disease remain unclear yet. Growth arrest specific 2 (GAS2) regulates multiple cellular functions including cell cycle, apoptosis and calpain activities. In the present study, we found GAS2 was up-regulated in CML cells including CD34+ progenitor cells compared to their normal counterparts. We utilized RNAi and the expression of dominant negative form of GAS2 (GAS2DN) to target GAS2, which resulted in calpain activity enhancement and growth inhibition of both K562 and MEG-01 cells. Targeting GAS2 also sensitized K562 cells to Imatinib mesylate (IM). GAS2DN suppressed the tumorigenic ability of MEG-01 cells and impaired the tumour growth as well. Moreover, the CD34+ cells from CML patients and healthy donors were transduced with control and GAS2DN lentiviral vectors, and the CD34+ transduced (YFP+) progeny cells (CD34+YFP+) were plated for colony-forming cell (CFC) assay. The results showed that GAS2DN inhibited the CFC production of CML cells by 57±3% (n = 3), while affected those of normal hematopoietic cells by 31±1% (n = 2). Next, we found the inhibition of CML cells by GAS2DN was dependent on calpain activity but not the degradation of beta-catenin. Lastly, we generated microarray data to identify the differentially expressed genes upon GAS2DN and validated that the expression of HNRPDL, PTK7 and UCHL5 was suppressed by GAS2DN. These 3 genes were up-regulated in CML cells compared to normal control cells and the growth of K562 cells was inhibited upon HNRPDL silence. Taken together, we have demonstrated that GAS2 is up-regulated in CML cells and the inhibition of GAS2 impairs the growth of CML cells, which indicates GAS2 is a novel regulator of CML cells and a potential therapeutic target of this disease.
Phenotypic characterization of mouse mammary epithelial stem and progenitor cells
J Stingl, CJ Eaves, CJ Watson
Breast Cancer Research , 2006, DOI: 10.1186/bcr1557
Abstract: This work is supported by Breast Cancer Campaign.
Two functionally distinct epithelial progenitors exist within the luminal cell compartment of the mouse mammary gland
J Stingl, CJ Eaves, CJ Watson
Breast Cancer Research , 2008, DOI: 10.1186/bcr1886
Abstract: To determine the cells that make up this hierarchy and the relationship between them, we used fluorescence-activated cell sorting in combination with in vitro colony-forming cell assays to examine the growth and differentiative properties of phenotypically distinct subsets of mouse mammary epithelial cells.Our results indicate that >95% of all colony-forming cells present within the mammary epithelium are localized within the luminal cell compartment and that >90% of these have a CD45-Ter119-CD31-(Lin-)CD24highCD14+phenotype. This progenitor cell population can be further resolved into two functionally distinct subpopulations based on the expression of Sca1. The Lin-CD24highCD14+Sca1- progenitors, which express low levels of estrogen receptor alpha and intermediate levels of keratin 14 (K14), are perceived to be progenitors that produce Lin-CD24highCD14-Sca1- alveolar cells during pregnancy. The Lin-CD24highCD14+Sca1+ progenitors, which express intermediate levels of estrogen receptor alpha and are K14-, are perceived to be precursors of the steroid receptor expressing cells, of which the vast majority are terminally differentiated and have a Lin-CD24highCD14-Sca1+ phenotype.These results demonstrate the existence of two functionally distinct progenitor cells within the luminal compartment of the mammary gland and provide a framework for interpreting breast tumour gene expression profiles and the possible origins of breast tumours.
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