Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Creighton, Chad J.; Chang‐Claude, Jenny; Rosen, Jeffrey M.

doi:10.1007/s10911-010-9173-1

Cited by 233 publications

(195 citation statements)

References 43 publications

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“…Most importantly, cancer stem cells (CSCs) derived from human breast cancer specimens are enriched for EMT markers (23). These and other similar observations (25) suggested that the EMT and CSC programs are intertwined and that acquisition of EMT traits by cancer cells is sufficient to bestow on them CSC characteristics. Because LOX was a critical regulator of EMT, we asked whether it played similar roles in regulating the CSC program in BCCs.…”

Section: Lox Does Not Mediate the Msc-induced Expansion Of Cancer Stemmentioning

confidence: 74%

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

El-Haibi

Bell

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

199

161

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Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSCinduced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells.

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Section: Lox Does Not Mediate the Msc-induced Expansion Of Cancer Stemmentioning

confidence: 74%

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

El-Haibi

Bell

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

199

161

View full text Add to dashboard Cite

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“…Claudin-2 and breast cancer liver metastasis S Tabariès et al by features of an epithelial-to-mesenchymal transition, enhanced stem cell characteristics and resistance to chemotherapy (Creighton et al, 2009(Creighton et al, , 2010Hennessy et al, 2009;Prat et al, 2010;Taube et al, 2010). At the present time, the status of claudin-2 expression within these 'claudin-low' tumors has not been described.…”

Section: Discussionmentioning

confidence: 89%

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

et al. 2010

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The liver represents the third most frequent site of metastasis in patients with breast cancer. We performed in vivo selection using 4T1 breast cancer cells to identify genes associated with the liver metastatic phenotype. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression, specifically in liver-aggressive breast cancer cells. We further demonstrate that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. The liver-aggressive breast cancer cells display a claudin-2-mediated increase in their ability to adhere to extracellular matrix (ECM) components, such as fibronectin and type IV collagen. Claudin-2 facilitates these cell/matrix interactions by increasing the cell surface expression of a 2 b 1 -and a 5 b 1 -integrin complexes in breast cancer cells. Indeed, claudin-2-mediated adhesion to fibronectin and type IV collagen can be blocked with neutralizing antibodies that target a 5 b 1 and a 2 b 1 complexes, respectively. Immunohistochemical analyses reveal that claudin-2, although weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Together, these results uncover novel roles for claudin-2 in promoting breast cancer adhesion to the ECM and define its importance during breast cancer metastasis to the liver.

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“…The epithelial mesenchymal transition (EMT) is an essential component of tumor progression and also plays a normal role in embryonic development, tissue remodeling and wound repair [1] . The occurrence of the EMT during tumor progression allows benign tumor cells to acquire three major changes in cellular phenotype.…”

Section: Introductionmentioning

confidence: 99%

Cross-regulation between protein L-isoaspartyl O-methyltransferase and ERK in epithelial mesenchymal transition of MDA-MB-231 cells

et al. 2011

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Aim: Protein L-isoaspartyl O-methyltransferase (PIMT) regulates cell adhesion in various cancer cell lines through activation of integrin αv and the PI3K pathway. The epithelial mesenchymal transition (EMT) enables epithelial cells to acquire the characteristics of mesenchymal cells, and to allow them to migrate for metastasis. Here, we examined the relationship between PIMT and EMT with attached or detached MDA-MB 231 cells. Methods: Human breast cancer cell line MDA-MB-231 cells were maintained in a suspension on poly-HEMA in the presence or absence of PIMT siRNA or ERK inhibitor PD98059. The mRNAs and proteins were analyzed using RT-PCR and immunoblotting, respectively. Results: During cellular incubation under detached conditions, PIMT, integrin αv and EMT proteins, such as Snail, Slug and matrix metalloproteinase 2 (MMP-2), were significantly increased in correlation with the phosphorylation of ERK1/2. The ERK inhibitor PD98059 (25 µmol/L) strongly suppressed the expression of the proteins and PIMT. Interestingly, PIMT siRNA blocked the phosphorylation of ERK and the expression of the EMT proteins. Additionally, PIMT and ERK phosphorylation were both co-activated by treatment with TGF-β (10 ng/mL) and TNF-α (10 ng/mL). Conclusion: A tight cross-regulation exists between ERK and PIMT in regards to their activation and expression during the EMT. Because the role of PIMT in the EMT and metastatic processes remains unclear, in this study, we explored the involvement of PIMT in the regulation of the detachment and attachment of the anoikis-resistant cell line MDA-MB-231, an aggressive breast cancer cell line with a highly invasive, migrative, and metastatic characters [10] , by culturing the cells in poly-HEMA (2-hydroxyethylmethacrylate)-coated dishes and introducing siRNA specific for PIMT. Materials and methods MaterialsLiCl and poly-HEMA were purchased from Sigma-Aldrich (St Louis, MO, USA). Dulbecco's modified Eagle's medium (DMEM), penicillin/streptomycin solution (10 000 unit/mL and 10 mg/mL, respectively), fetal bovine serum (FBS) and Dulbecco's phosphate-buffered saline (DPBS) were purchased from Gibco BRL (Gaithersburg, MD, USA). MDA-MB 231 cells were obtained from American Type Culture Collection (Manassas, VA, USA). Moloney murine leukemia virus (M-MLV) reverse transcriptase, polymerase chain reaction (PCR) premix, and Sapphire Super Taq were purchased from Rexgene Biotech Co, Ltd (Ochang, Korea). All primers used for PCR were purchased from Bioneer (Taejeon, Korea). A mixture of Stealth TM /siRNA duplex oligoribonucleotides against PIMT and Lipofectamine TM RNAiMAX was purchased from Invitrogen (Carlsbad, CA, USA). Rabbit anti-PIMT antiserum was produced against recombinant PIMT proteins of porcine brain as previously described (Koh and Hong, unpublished data). Antibodies against MAPK, MMP-2, MMP-9, N-cadherin, integrin αv, phospho-GSK3 (Tyr 279/216 ), phospho-ERK1/2 (Thr 202 /Tyr 204 ), phospho-MEK1 (Ser 218/222 )/MEK2 (Ser 222/226 ), phospho-Akt1/PkBα (Ser 473 ) and phospho-p90RSK (Ser 380 ) were...

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Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Cited by 233 publications

References 43 publications

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

Cross-regulation between protein L-isoaspartyl O-methyltransferase and ERK in epithelial mesenchymal transition of MDA-MB-231 cells

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