Dormant Wnt-Initiated Mammary Cancer Can Participate in Reconstituting Functional Mammary Glands

Gestl, Shelley A.; Leonard, Travis L.; Biddle, Jessica L.; Debies, Michael T.; Gunther, Edward J.

doi:10.1128/mcb.01525-06

Cited by 14 publications

(7 citation statements)

References 42 publications

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“…For example, chronic infection of certain mouse lines with mouse mammary tumor virus (MMTV) induces mammary tumors with frequent transcriptional activation of Wnt-1 (Int-1), Wnt-3, and Wnt-10b [100]. Transgenic expression of Wnt-1 [101] or Wnt-10b [102] under the control of the MMTV LTR results in precocious lobuloalveolar development and differentiation in both male and female mice, and induces hyperplasias and adenocarcinomas; similar phenotypes have been observed in mice that carry an inducible Wnt-1 transgene [103,104]. In the case of MMTV-Wnt-1 transgenic mice, epithelial hyperplasia is noticeable in the embryonic mammary ducts [105].…”

Section: Aberrant Activation Of Wnt Signaling Induces Breast Cancer mentioning

confidence: 67%

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Wnt Signaling, Stem Cells, and the Cellular Origin of Breast Cancer

Williams

2007

Stem Cell Rev

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The breast epithelium comprises cells at different stages of differentiation, including stem cells, progenitor cells, and more differentiated epithelial and myoepithelial cells. Wnt signaling plays a critical role in regulating stem/progenitor cells in the mammary gland as well as other tissue compartments. Furthermore, there is strong evidence suggesting that aberrant activation of Wnt signaling induces mammary tumors from stem/progenitor cells, and that Wnt exerts its oncogenic effects through LRP5/6-mediated activation of beta-catenin and mTOR pathways. Recent studies using avian retrovirus-mediated introduction of oncogenes into a small subset of somatic mammary cells suggest that polyoma middle T antigen (PyMT) may also preferentially transform stem/progenitor cells. These observations suggest that stem/progenitor cells in the mammary gland may be especially susceptible to oncogenic transformation. Whether more differentiated cells may also be transformed by particular oncogenes is actively debated; it is presently unclear whether stem cells or differentiated mammary cells are more susceptible to transformation by individual oncogenes. Better stem cell and progenitor cell markers as well as the ability to specifically target oncogenes into different mammary cell types will be needed to determine the spectrum of oncogene transformation for stem cells versus more differentiated cells.

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Section: Aberrant Activation Of Wnt Signaling Induces Breast Cancer mentioning

confidence: 67%

“…Wnt-1-induced mammary tumors indeed contain both epithelial and myoepithelial cells [104,109,110,115,116] and the two cell types share a common mutation in Pten [109] or HRas (Katrina Podsypanina, personal communication), implying an origin in a bipotential progenitor cell.…”

Section: Aberrant Activation Of Wnt Signaling Induces Breast Cancer mentioning

confidence: 96%

Wnt Signaling, Stem Cells, and the Cellular Origin of Breast Cancer

Williams

2007

Stem Cell Rev

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“…Activation of the Wnt/β-catenin pathway has been shown to increase self-renewal of both normal hematopoietic stem cells 8 and the progenitor cells from patients with chronic myelogenous leukemia 35 and other tumors. [36][37][38][39][40] Our findings point to an importance of GSK-3β in the pathogenesis of AML.…”

Section: Discussionmentioning

confidence: 99%

Wnt/ -catenin Pathway Modulates the Sensitivity of the Mutant FLT3 Receptor Kinase Inhibitors in a GSK-3 Dependent Manner

Jiang¹,

Griffin²

2010

Genes & Cancer

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The FLT3 tyrosine kinase receptor is involved in both hematopoiesis and hematological malignancies. The Wnt/β-catenin pathway has been shown to participate in the self-renewal of hematopoietic stem cells and to cooperate with the mutant FLT3 receptors in leukemic transformation. However, the detailed biological impact of such a constitutively activated Wnt pathway remains to be further explored. Here, the authors report that activating mutations of FLT3 constitutively activate β-catenin by inhibition of GSK-3β in a PI3 kinase pathway-dependent manner. Ectopic expression of a dominant negative form of GSK-3β in FLT3-ITD-expressing cells activated β-catenin and blocked the downregulation of the TCF/β-catenin transcriptional activity induced by inhibition of FLT3 kinase. Furthermore, inhibition of cell proliferation and colony formation induced by such suppression of FLT3 kinase activity could be partially reversed by knockdown of GSK-3β and restored by knockdown of either TCF4 or β-catenin. Moreover, exogenous activation of the Wnt pathway also attenuated such inhibitory effect. These findings indicate that the potencies of the inhibitors of FLT3 kinase activity could be modulated by the activity of the Wnt/β-catenin pathway in the cells harboring FLT3-ITD mutations, and FLT3-ITDs signal through GSK-3β to activate β-catenin that this is likely to directly contribute to the leukemic phenotype.

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“…b Loss of a surface receptor (for example, uPAR, α5β1 integrin or EGFR) that transduces growth signals from the microenvironment (for example, fibronectin) results in stress signalling (low FAK-Ras-ERK, and high CDC42 (cell division cycle 42)-p38 activity; middle panel), which in turn might lead to dormancy. This is one example to illustrate the theme of crosstalk between the microenvironment and/or receptor signalling in cellular dormancy (for others see REFS 20,21,29,56,84,124,125). It is likely that other unidentified pathways are also involved.…”

Section: Abc Transportersmentioning

confidence: 96%

Models, mechanisms and clinical evidence for cancer dormancy

2007

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Patients with cancer can develop recurrent metastatic disease with latency periods that range from years even to decades. This pause can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic. Cancer dormancy is poorly understood, resulting in major shortcomings in our understanding of the full complexity of the disease. Here, I review experimental and clinical evidence that supports the existence of various mechanisms of cancer dormancy including angiogenic dormancy, cellular dormancy (G0-G1 arrest) and immunosurveillance. The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted.The vast majority of cancer-related deaths are due to metastatic tumour growth that impairs the function of vital organs 1 . Metastatic lesions invariably originate from disseminated tumour cells, which often undergo a period of dormancy 2 (FIG. 1). Cancer recurrence after therapy and long periods of remission is frequent. For example, 20-45% of patients with breast or prostate cancer will relapse years or decades later 3-5 (FIGS 1,2). In fact, most cancer types are associated with disseminated disease that after treatment might persist as minimal residual disease (FIG 2; TABLE 1). However, the lack of mechanistic insight into this stage has been a major shortcoming in our understanding of the full complexities of metastatic growth. Functional characterization of disseminated dormant tumour cells is important because these cells most probably contain the information about the future progression of the disease (that is, metastasis development). To fully understand dormancy, cells must be characterized during the dormant state. Therefore, given that these cells are present in a wide variety of cancers, information gathered from studies of cancer dormancy might be applicable to a large number of patients.Cancer dormancy can be separated into mechanisms that antagonize the expansion of a dividing tumour cell population (tumour mass dormancy) and mechanisms that result in tumour cell growth arrest (tumour cell dormancy, or cellular dormancy) (FIG. 2). In the former, tumour cells usually divide but the lesion does not expand beyond a certain size because of either limitations in blood supply or an active immune system. Cellular dormancy can occur when tumour cells enter a state of quiescence (see BOX 1 for information on the relationship between quiescence, senescence and dormancy). These general mechanisms might explain the dormancy of residual cells that, following treatment, develop loco-regional or distant organ recurrences within different time frames. Box 1 Cancer dormancy: senescence or quiescence programmes?A common attempt to explain cellular dormancy is to catalogue it within known mechanisms of growth arrest such as senescence or quiescence. However, whether quiescence or senescence programmes drive tumour cell dormancy is still incompletely understood. NIH Public Access Author Ma...

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Dormant Wnt-Initiated Mammary Cancer Can Participate in Reconstituting Functional Mammary Glands

Cited by 14 publications

References 42 publications

Wnt Signaling, Stem Cells, and the Cellular Origin of Breast Cancer

Wnt Signaling, Stem Cells, and the Cellular Origin of Breast Cancer

Wnt/ -catenin Pathway Modulates the Sensitivity of the Mutant FLT3 Receptor Kinase Inhibitors in a GSK-3 Dependent Manner

Models, mechanisms and clinical evidence for cancer dormancy

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