Twist2 contributes to breast cancer progression by promoting an epithelial–mesenchymal transition and cancer stem-like cell self-renewal

Fang, Xiaoguang; Cai, Yuan-Rong; Liu, J; Wang, Z; Wu, Qiu-Wan; Zhang, Z; Yang, Chaoyong; Yuan, Liang; Ouyang, Gaoliang

doi:10.1038/onc.2011.181

Cited by 169 publications

(144 citation statements)

References 59 publications

(66 reference statements)

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“…We tested this idea by growing multicellular structures from Michigan Cancer Foundation-7 (MCF-7) cells and then quantifying the extent of line formation and disorganization. The MCF-7 cell line was originally derived from a patient with invasive ductal carcinoma, represents an advanced stage of tumor progression (37,38), and has further compromised integrity of cell-cell adhesion (39,40). When grown, extracted, and deposited on collagen 1 like the MCF10AT acini, the MCF-7 spheroids more readily spread, as expected.…”

Section: Significancementioning

confidence: 68%

Rapid disorganization of mechanically interacting systems of mammary acini

Shi

Ghosh

Engelke

et al. 2013

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

138

177

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Cells and multicellular structures can mechanically align and concentrate fibers in their ECM environment and can sense and respond to mechanical cues by differentiating, branching, or disorganizing. Here we show that mammary acini with compromised structural integrity can interconnect by forming long collagen lines. These collagen lines then coordinate and accelerate transition to an invasive phenotype. Interacting acini begin to disorganize within 12.5 ± 4.7 h in a spatially coordinated manner, whereas acini that do not interact mechanically with other acini disorganize more slowly (in 21.8 ± 4.1 h) and to a lesser extent (P < 0.0001). When the directed mechanical connections between acini were cut with a laser, the acini reverted to a slowly disorganizing phenotype. When acini were fully mechanically isolated from other acini and also from the bulk gel by box-cuts with a side length <900 μm, transition to an invasive phenotype was blocked in 20 of 20 experiments, regardless of waiting time. Thus, pairs or groups of mammary acini can interact mechanically over long distances through the collagen matrix, and these directed mechanical interactions facilitate transition to an invasive phenotype.mechanobiology | cancer E pithelial cells are physically coupled to their neighbors and are also in contact with the ECM. The ECM confers mechanical integrity to tissues and provides chemical, anatomical, and mechanical signals to cells, influencing differentiation, development, and pathogenesis (1-11). The extent to which mechanical cues are generated and received by individual cells has been studied both experimentally and theoretically (12)(13)(14). Progress has also been made in understanding the signaling pathways that cells use to sense external mechanics. Cell-ECM interactions are mediated in part by transmembrane proteins typified by the integrins, which link the cell's internal actin cytoskeleton with extracellular collagen fibers (15). Cells use multiple approaches for integrating mechanical cues with biochemical cues provided by soluble factors; for example, there is extensive multilayered cross-talk between integrin and TGF-β signaling (16,17). It is now also clear that key developmental regulators, such as Notch, can be directly activated by mechanical force (18,19).Less is known about the interactions of organized multicellular structures with the ECM and how those interactions affect tissue architecture, composition, and stability, as well as the molecular pathways by which these effects are mediated. In certain situations, contractile multicellular structures are able to mechanically reorganize biopolymer networks over long distances and in a highly directional manner, generating what are variously referred to as fibers, tracts, cables, straps, or lines. Regions of highly directional collagen alignment and concentration have been seen in systems ranging from single cells and tumor explants to human clinical samples (6,8,10,(20)(21)(22). Vader et al. demonstrated that the formation of long collagen lines is ...

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Section: Significancementioning

confidence: 68%

Rapid disorganization of mechanically interacting systems of mammary acini

Shi

Ghosh

Engelke

et al. 2013

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

138

177

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“…3e23h). Consistent regulation of the EMTrelated genes (such as SNAIL, MTA3, AKT1 and LOXL2) [16][17][18][19][20][21] by NEDD9 was validated in both lung cancer cell lines with either NEDD9 overexpression or NEDD9 knockdown (Supporting Information Figs. 6a-6d).…”

Section: Nedd9 Promotes Partial Emt Process Of Lung Cancer Cellsmentioning

confidence: 81%

NEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition

Jin

Zheng

et al. 2013

Int. J. Cancer

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Metastasis is the major cause for high mortality of lung cancer with the underlying mechanisms poorly understood. The scaffolding protein neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) has been identified as a prometastasis gene in several types of cancers including melanoma and breast cancer. However, the exact role and related mechanism of NEDD9 in regulating lung cancer metastasis still remain largely unknown. Here, we demonstrate that NEDD9 knockdown significantly inhibits migration, invasion and metastasis of lung cancer cells in vitro and in vivo. The pro-metastasis role of Nedd9 in lung cancer is further supported by studies in mice models of spontaneous cancer metastasis. Moreover, we find that NEDD9 promotes lung cancer cell migration and invasion through the induction of epithelial-mesenchymal transition (EMT) potentially via focal adhesion kinase activation. More importantly, NEDD9 expression inversely correlates with Ecadherin expression in human lung cancer specimens, consistent with the findings from in vitro studies. Taken together, this study highlights that NEDD9 is an important mediator promotes lung cancer metastasis via EMT.Lung cancer is a deadly disease with high mortality and its 5-year survival rate is approximately 15% globally. Metastasis, frequently observed in patients initially diagnosed with lung cancer, remains as an important factor in contribution to high mortality of lung cancer.1 Despite great efforts in last decades, the molecular mechanisms involved in lung cancer metastasis process still remain far from being fully understood.Recent studies have shown that NEDD9 (Neural precursor cell expressed, developmentally down-regulated 9, also known as HEF1), a scaffolding protein without known catalytic activity, is important for pro-metastasis behavior in several types of solid tumors. 2,3 In melanoma, NEDD9 is frequently up-regulated by gene allele amplification and activates FAK (focal adhesion kinase) to promote cell invasion and metastasis.2 NEDD9 complexes with DOCK3 and regulates the activation of Rac which are essential for promoting the mesenchymal-type movement of melanoma cells. 4 In glioblastoma, NEDD9 works as an effector of FAK to promote tumor cell aggression.5 Interestingly, Nedd9 2/2 mice displayed much less mammary tumor formation as well as lung metastasis, which is potentially due to the reduction of Fak and Src activation.6 Consistently, we have recently found that NEDD9 is transcriptionally regulated by CRTC1/CREB complex in LKB1-deficient lung cancer and significantly contributes to tumor progression via the promotion of tumor differentiation status.7 However, the roles of NEDD9 in lung

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“…5b). It has been shown that E-cadherin expression in breast cancer cells is regulated at the level of mRNA transcription by transcription factors important for EMT such as ZEB1, Twist, Snail, and Slug [13][14][15] or by epigenetic mechanisms [16,17]; however, E-cadherin mRNA levels were not altered by E+ R5020 treatment in T47D cells (Fig. 5c).…”

Section: E+ps Treatment Decreases E-cadherin Protein In Breast Cancermentioning

confidence: 92%

“…The decrease or loss of E-cadherin protein is associated with poor prognosis in breast cancer patients [12]. Numerous studies have reported that E-cadherin mRNA expression is negatively regulated by transcription factors important for epithelial-to-mesenchymal transition (EMT) [13][14][15]. Based on in vitro studies, it has been proposed that cells composing ductal carcinoma in situ undergo EMT that is accompanied with decreased E-cadherin expression and become invasive.…”

Section: Introductionmentioning

confidence: 99%

Progesterone Decreases Levels of the Adhesion Protein E-Cadherin and Promotes Invasiveness of Steroid Receptor Positive Breast Cancers

et al. 2013

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Progestins are reported to increase the risk of invasive breast cancers in postmenopausal women receiving hormone therapy with estrogen plus progestin. We report here that estrogen and progesterone receptor positive (ER+PR+) rat mammary tumors arising in the presence of estrogen and progesterone exhibit increased invasiveness and decreased expression of E-cadherin protein compared with tumors growing in the presence of estrogen alone. A similar decrease of Ecadherin expression was observed in human ER+PR+ invasive ductal carcinoma compared with ductal carcinoma in situ. In agreement with findings in the rat, estrogen plus progestin R5020 treatment decreased E-cadherin expression in vitro in T47D human breast cancer cells. Decrease of E-cadherin protein was mediated by progesterone receptor B (PRB) and dependent on the activation of the Wnt pathway. These results suggest that progesterone signaling via PRB contributes to tumor invasiveness and can provide an important therapeutic target for treatment of invasive ER+PR+ breast cancers.

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Twist2 contributes to breast cancer progression by promoting an epithelial–mesenchymal transition and cancer stem-like cell self-renewal

Cited by 169 publications

References 59 publications

Rapid disorganization of mechanically interacting systems of mammary acini

Rapid disorganization of mechanically interacting systems of mammary acini

NEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition

Progesterone Decreases Levels of the Adhesion Protein E-Cadherin and Promotes Invasiveness of Steroid Receptor Positive Breast Cancers

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