Nuclear Factor-κB Enhances ErbB2-Induced Mammary Tumorigenesis and Neoangiogenesis in Vivo

Liu, Manran; Ju, Xiaoming; Willmarth, Nicole E.; Casimiro, Mathew C.; Ojeifo, John; Sakamaki, Toshiyuki; Katiyar, Sanjay; Jiao, Xuanmao; Попов, В. М.; Yu, Zuoren; Wu, Kongming; Joyce, David A.; Wang, Chenguang; Pestell, Richard G.

doi:10.2353/ajpath.2009.080706

Cited by 45 publications

(42 citation statements)

References 48 publications

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“…Thus, unlike previous reports on the effects of Stat3 (4) and components of the IKK/NF-kB pathway (24,25) in ErbB2 tumors, loss of Bcl3 did not affect mammary tumor growth in vivo.…”

Section: Bcl3 Is Elevated In Erbb2-positive Mammary Tumor Cells But Dcontrasting

confidence: 48%

Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors

et al. 2013

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Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumors. Studies in cell lines suggest that its oncogenic effects are mediated through the induction of proliferation and inhibition of cell death, yet its role in endogenous solid tumors has not been established. Here, we address the oncogenic effect of Bcl3 in vivo and describe how this Stat3-responsive oncogene promotes metastasis of ErbB2-positive mammary tumors without affecting primary tumor growth or normal mammary function. Deletion of the Bcl3 gene in ErbB2-positive (MMTV-Neu) mice resulted in a 75% reduction in metastatic tumor burden in the lungs with a 3.6-fold decrease in cell turnover index in these secondary lesions with no significant effect on primary mammary tumor growth, cyclin D1 levels, or caspase-3 activity. Direct inhibition of Bcl3 by siRNA in a transplantation model of an Erbb2-positive mammary tumor cell line confirmed the effect of Bcl3 in malignancy, suggesting that the effect of Bcl3 was intrinsic to the tumor cells. Bcl3 knockdown resulted in a 61% decrease in tumor cell motility and a concomitant increase in the cell migration inhibitors Nme1, Nme2, and Nme3, the GDP dissociation inhibitor Arhgdib, and the metalloprotease inhibitors Timp1 and Timp2. Independent knockdown of Nme1, Nme2, and Arhgdib partially rescued the Bcl3 motility phenotype. These results indicate for the first time a cell-autonomous disease-modifying role for Bcl3 in vivo, affecting metastatic disease progression rather than primary tumor growth. Cancer Res; 73(2); 745-55. Ó2012 AACR.

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“…Thus, unlike previous reports on the effects of Stat3 (4) and components of the IKK/NF-kB pathway (24,25) in ErbB2 tumors, loss of Bcl3 did not affect mammary tumor growth in vivo.…”

Section: Bcl3 Is Elevated In Erbb2-positive Mammary Tumor Cells But Dcontrasting

confidence: 48%

Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors

et al. 2013

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“…80 NF-B activity enhanced ErbB2-mediated mammary tumorigenesis in vivo by promoting growth and survival signaling via the heterotypic secretion of vascular endothelial growth factor (VEGF) and the induction of tumor vasculogenesis. 81 The tumorigenic function of NF-B in the normally developed adult mammary gland of immunocompetent mice was recently analyzed. 49 In vivo inducible expression of IB␣SR in the adult mammary epithelium delayed the onset and number of new tumors.…”

Section: Nf-bmentioning

confidence: 99%

The Role of Breast Cancer Stem Cells in Metastasis and Therapeutic Implications

Velasco-Velázquez

Попов

Lisanti

et al. 2011

The American Journal of Pathology

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Cancer stem cells (CSCs) are tumor cells that possess the capacity to divide asymmetrically, producing one stem cell (self-renewal) and one progenitor cell that is able to generate heterogeneous lineages of the cancer cells that comprise tumors. CSCs in human breast tumors were initially identified in 2003 by Al-Hajj et al, 1 who discovered a cellular population characterized by the cell-surface markers CD44 ϩ /CD24 Ϫ/low /ESA ϩ and lack of expression of CD2, CD3, CD10, CD16, CD18, CD31, CD64, and CD140b (lineage Ϫ ). As few as 200 of these cells were able to form tumors when xenotransplanted into NOD/SCID mice, whereas tens of thousands of other cells could not.1 The tumors generated recapitulated the phenotypic heterogeneity of the parental tumor, containing a minority of CD44 ϩ /CD24 Ϫ/low /lineage Ϫ cells that can be serially passaged to form new tumors.1 The CD44 ϩ /CD24 Ϫ phenotype has been used extensively to identify and isolate breast cancer cells with increased tumorigenicity.Putative breast CSCs have also been isolated from patient samples after in vitro propagation and from breast cancer cell lines, through their ability to proliferate in suspension as nonadherent spheres (mammospheres). 1-4Because the capacity to form mammospheres is increased in early progenitor/stem cells, this system has been widely used as an indirect measurement of the number of cells with self-renewal capability. 5,6 In accord with in vivo data, mammospheres from breast cancer cells are enriched in cells with the CD44 ϩ /CD24 /CD24Ϫ retain self-renewal capability, other markers for human breast CSCs have been investigated. Activity of the aldehyde dehydrogenase (ALDH) family of cytosolic isoenzymes is inSupported in part by PASPA-UNAM (Programa de Apoyos para la Superación del Personal Académico-Universidad Nacional Autónoma de México) (M.A.V.-V.) and the NIH (grants R01CA070896, R01CA075503, R01CA107382, R01CA132115, and R01CA086072 to R.G.P. and R01CA120876 to M.P.L.). The Kimmel Cancer Center was supported by an NIH cancer center core grant (P30CA56036 to R.G.P.). This project is funded in part from the Marian C. Falk Medical Research Trust and a grant from the Pennsylvania Department of Health (R.G.P.).

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“…Cell migration and invasion assays were performed as we described previously. (35) For invasion assay, 2.5 9 10 4 cells were seeded on an 8-lm-pore size Transwell filter insert (Corning Inc, Corning, NY, USA) coated with extracellular matrix (ECM) (1:7.5) (Sigma), while cell migration assay did not coat with ECM. After 48 h of incubation at 37°C and 5% CO 2 , cells adherent to the upper surface of the filter were removed.…”

Section: Facs Of Cd44 + /Cd24mentioning

confidence: 99%

“…Western blot analysis was conducted as per our previous study. (35) Briefly, the protein was separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) (8%, 10% or 12%) and transferred to polyvinylidene fluoride (PVDF) membranes. Non-specific binding sites were blocked by incubating with tris buffered saline with tween 20 (TBST) containing 5% (w/v) non-fat dried milk.…”

Section: Facs Of Cd44 + /Cd24mentioning

confidence: 99%

MiR‐21 regulates epithelial‐mesenchymal transition phenotype and hypoxia‐inducible factor‐1α expression in third‐sphere forming breast cancer stem cell‐like cells

et al. 2012

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Cancer stem cells (CSCs) are predicted to be critical drivers of tumor progression due to their "stemness", but the molecular mechanism of CSCs in regulating metastasis remains to be elucidated. Epithelial-mesenchymal transition (EMT), hypoxia-inducible factor (HIF)-1a, and miR-21, all of which contribute to cell migration for metastasis, are interrelated with CSCs. In the present study, third-sphere forming (3-S) CSC-like cells, which showed elevated CSC surface markers (ALDH1 + and CD44) and sphereforming capacity as well as migration and invasion capacities, were cultured and isolated from breast cancer MCF-7 parental cells, to evaluate the role of miR-21 in regulating the CSC-like cell biological features, especially EMT. EMT, which was assessed by overexpression of mesenchymal cell markers (N-cadherin, Vimentin, alpha-smooth muscle actin [a-SMA]) and suppression of epithelial cell marker (E-cadherin), was induced in 3-S CSC-like cells. Moreover, both of HIF-1a and miR-21 were upregulated in the CSC-like cells. Interestingly, antagonism of miR-21 by antagomir led to reversal of EMT, downexpression of HIF-1a, as well as suppression of invasion and migration, which indicates a key role of miR-21 involved in regulate CSC-associated features. In conclusion, we demonstrated that the formation of CSC-like cells undergoing process of EMT-like associated with overexpression of HIF-1a, both of which are regulated by miR-21. (Cancer Sci 2012; 103: 1058-1064 C ancer stem cells (CSCs) are predicted to be the cell origin of the tumor and responsible for tumor progression, relapse and metastasis due to their self-renewal capacity and limitless proliferative potential, as well as invasion and migration capacity.(1-5) Therefore, the development of successful cancer therapeutic regimen requires targeting the CSCs, such as the elucidation of molecular pathways, which regulate CSC features.Recently, breast cancer cells forming mammospheres in suspension cultures were generally acknowledged as breast cancer CSCs (bCSCs) due to their self-renewal capacity, (6,7) while mammospheres were also accepted as bCSC-like cell models, enriching bCSCs. Besides, bCSCs also could be identified and isolated according to cell surface markers such as aldehyde dehydrogenase 1 + (ALDH1 (1) But now, the isolation and culture of high-purity bCSC model is still one of the "choke points" in bCSC research.For most epithelial tumors, including breast cancer, progression toward malignancy is accompanied by a process of epithelial-mesenchymal transition (EMT), which is characterized by a loss of epithelial differentiation and a shift towards mesenchymal phenotype.(8) The EMT towards a more mesenchymal phenotype involves downexpression of epithelial markers (e.g. E-cadherin and Keratins) and upexpression of mesenchymal markers (e.g. N-cadherin, Vimentin, alphasmooth muscle actin [a-SMA]), as well as increased cell mobility and invasive phenotype.(9-11) Accumulating evidence demonstrated that the induction of EMT in vitro in transformed mammary epithelial...

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Nuclear Factor-κB Enhances ErbB2-Induced Mammary Tumorigenesis and Neoangiogenesis in Vivo

Cited by 45 publications

References 48 publications

Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors

Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors

The Role of Breast Cancer Stem Cells in Metastasis and Therapeutic Implications

MiR‐21 regulates epithelial‐mesenchymal transition phenotype and hypoxia‐inducible factor‐1α expression in third‐sphere forming breast cancer stem cell‐like cells

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