Stem Cell Characteristics of Transplanted Rat Mammary Clonogens

Kim, Nam Deuk; Oberley, Terry D.; Yasukawa-Barnes, Jane; Clifton, Kelly H.

doi:10.1006/excr.2000.5013

Cited by 18 publications

(10 citation statements)

References 43 publications

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“…We hypothesized that up-regulation of Wip1 probably provides a selective advantage for the clonal expansion of cancer cells. It is now becoming clear that a subgroup of cells in mammary tumors possesses tumor-initiating cell function and contributes to tumor expansion and growth(32–35). The tumor-initiating cells, or cancer stem cells, can be isolated using cell surface markers or can be enriched in non-adherent mammospheres.…”

Section: Resultsmentioning

confidence: 99%

Oncogenic Wip1 Phosphatase Is Inhibited by miR-16 in the DNA Damage Signaling Pathway

et al. 2010

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Wild-type p53-induced phosphatase 1 (Wip1) was identified as an oncogene amplified and overexpressed in several human cancers. Recent evidence suggested that Wip1 is a critical inhibitor in the ATM/ATR-p53 DNA damage signaling pathway. Wip1 dephosphorylates several key DNA damage-responsive proteins and reverses DNA damage-induced cell cycle checkpoints. Previous reports showed that Wip1 was transcriptionally induced by p53 at the early stage of the DNA damage response. To investigate the temporal and functional regulation of Wip1, we identified a microRNA, miR-16, that specifically targets the mRNA of Wip1 and thus negatively regulates the expression level of Wip1. miR-16 itself is induced immediately after DNA damage. Therefore, the increase in Wip1 protein level is significantly postponed compared with that of its mRNA level, preventing a premature inactivation of ATM/ATR signaling and allowing a functional completion of the early DNA damage response. To better understand miR-16 biological functions in the context of cancer cells, we examined its expression in mammary tumor stem cells and found it to be markedly downregulated in mammary tumor stem cells. Overexpression of miR-16 or inhibition of Wip1 suppresses the self-renewal and growth of mouse mammary tumor stem cells and sensitizes MCF-7 human breast cancer cells to the chemotherapeutic drug doxorubicin. Together, our results suggest an important role of miR-16 in the regulation of Wip1 phosphatase in the DNA damage response and mammary tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Oncogenic Wip1 Phosphatase Is Inhibited by miR-16 in the DNA Damage Signaling Pathway

et al. 2010

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“…The existence of self-renewing multipotent mammary stem cells has been clearly demonstrated by transplantation studies in mice and rats [16-18]. Fragments of mammary epithelium marked with mouse mammary tumor virus were able to regenerate a new gland after transplantation into a mammary fat pad cleared of its epithelial components [19].…”

Section: Mammary Stem Cellsmentioning

confidence: 99%

Mammary stem cells, self-renewal pathways, and carcinogenesis

2005

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Bmi-1 = B lymphoma Mo-MLV insertion region 1; Dsh = Dishevelled; ESA = epithelial-specific antigen; Fu = Fused; GSK = glycogen synthase kinase; HBEC = human breast epithelial cell; Ihh = indian hedgehog; Ptch = patched; Shh = sonic hedgehog; Smo = smoothened; SuFu = suppressor of fused. Breast Cancer Research May 2005 Vol 7 No 3 Liu et al. AbstractThe mammary gland epithelial components are thought to arise from stem cells that undergo both self-renewal and differentiation. Self-renewal has been shown to be regulated by the Hedgehog, Notch, and Wnt pathways and the transcription factor B lymphoma Mo-MLV insertion region 1 (Bmi-1). We review data about the existence of stem cells in the mammary gland and the pathways regulating the self-renewal of these cells. We present evidence that deregulation of the self-renewal in stem cells/progenitors might be a key event in mammary carcinogenesis. If 'tumor stem cells' are inherently resistant to current therapies, targeting stem cell self-renewal pathways might provide a novel approach for breast cancer treatment.

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“…In quantitative rat mammary cell transplantation studies, both alveolar and ductal colonies were developed that support the conclusion that both colony types are derived from a single clonogenic mammary cell [10,11]. …”

Section: Introductionmentioning

confidence: 98%

Mammary cancer and epithelial stem cells: a problem or a solution?

Smith

2002

Breast Cancer Res

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LacZ = β-galactosidase (Escherichia coli); TGF-β1 = transforming growth factor-beta 1; WAP = whey acidic protein.Available online http://breast-cancer-research.com/content/4/2/047 IntroductionEvidence for mammary epithelial stem cells derives from studies of the glands from rodents, canines and humans. In the human, genetic analysis [1] of contiguous portions of individual human mammary ducts within the same breast signifies their clonal derivation and forecasts the existence of multipotent mammary epithelial cells in the human breast [2][3][4]. This work was confirmed and extended by the demonstration of a common loss of heterozygosity in normal cells in individual lobules within breast tissue from patients with carcinoma, in duct-lobular units from paraffin-embedded mammary tissue, and from normal luminal and myoepithelial cell clones derived from reduction mammoplasty patients [5][6][7].Cell lines from canine mammary spindle-cell tumors exhibited mixed phenotypes on transplantation but possessed identical allelic patterns in microsatellite analysis, suggesting that canine mammary tumors arise from pluripotent stem cells [8].Rat mammary glands contain a subpopulation of clonogenic epithelial cells that, when transplanted, give rise either to alveolar or ductal structures [9]. In quantitative rat mammary cell transplantation studies, both alveolar and ductal colonies were developed that support the conclusion that both colony types are derived from a single clonogenic mammary cell [10,11].In the mouse, it was recently shown that the epithelial population of a fully developed lactating mammary outgrowth in mice could consist of the progeny from a single cell [12]. Serial transplantation of epithelial fragments from the clonally derived gland demonstrated that the subsequently generated outgrowths are also comprised of progeny from the original antecedent. All epithelial cell types were found to be present within these clonal normal populations including luminal, myoepithelial, ductal and lobule-committed epithelial progenitors and fully competent mammary epithelial stem cells. These observations demonstrate the presence of multipotent AbstractThe existing paradigms for stem cells in adult tissues include the integument, the alimentary canal, the lung, the liver, skeletal muscle and bone marrow. The mammary gland, by contrast, is the 'new kid on the block'. What little is known about stem cells in the mammary gland indicates that they possess a prodigious capacity for self-renewal. More importantly, in rodents, they persist with undiminished reproductive vigor throughout the organism's lifetime without regard to age or reproductive history. Do these stem cells represent primary targets for mammary neoplasia? If so, what are the implications for prevention/therapy?

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Stem Cell Characteristics of Transplanted Rat Mammary Clonogens

Cited by 18 publications

References 43 publications

Oncogenic Wip1 Phosphatase Is Inhibited by miR-16 in the DNA Damage Signaling Pathway

Oncogenic Wip1 Phosphatase Is Inhibited by miR-16 in the DNA Damage Signaling Pathway

Mammary stem cells, self-renewal pathways, and carcinogenesis

Mammary cancer and epithelial stem cells: a problem or a solution?

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