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PMID:17332325

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Citation

Cheng, GZ, Chan, J, Wang, Q, Zhang, W, Sun, CD and Wang, LH (2007) Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 67:1979-87

Abstract

Metastasis, the cardinal feature of malignant tumors, is an important clinical variable in patient prognosis. To understand the basis for metastasis, we systematically selected for highly invasive cells from breast cancer cell lines, MCF7 and MDA-MB-453, with moderate to low invasive ability using Boyden chamber invasion assay. The four-cycle selected invasive lines, named MCF7-I4 and MDA-MB-453-I4, respectively, displayed epithelial-mesenchymal transition (EMT) and dramatically enhanced invasive ability. EMT changes were corroborated with decreased level of E-cadherin and increased vimentin, fibronectin, and beta(1) integrin. Twist, a basic helix-loop-helix transcription factor, and AKT2, a known proto-oncogene, were found to be elevated in the invasive cells compared with the parental. Ectopic expression and knockdown of Twist by short interference RNA resulted in significant increase and reduction, respectively, of AKT2 protein and mRNA expression. Twist bound to E-box elements on AKT2 promoter and enhanced its transcriptional activity. Moreover, silencing AKT2 decreased Twist-promoted migration, invasion, and paclitaxel resistance. Reintroducing AKT2 largely rescued the phenotype resulted from knockdown of Twist in I4 cells, suggesting that AKT2 is a downstream target and functional mediator of Twist. Finally, we observed a 68.8% correlation of elevated Twist and AKT2 expression in late-stage breast cancers as oppose to 13% in early-stage breast cancers. Our study identifies Twist as a positive transcriptional regulator of AKT2 expression, and Twist-AKT2 signaling is involved in promoting invasive ability and survival of breast cancer cells.

Links

PubMed Online version:10.1158/0008-5472.CAN-06-1479

Keywords

Antineoplastic Agents, Phytogenic/pharmacology; Antineoplastic Agents, Phytogenic/therapeutic use; Breast Neoplasms/drug therapy; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Cell Movement/drug effects; Drug Resistance, Neoplasm/drug effects; Gene Expression Regulation, Neoplastic/drug effects; Humans; Neoplasm Invasiveness; Nuclear Proteins/antagonists & inhibitors; Nuclear Proteins/metabolism; Nuclear Proteins/physiology; Paclitaxel/pharmacology; Paclitaxel/therapeutic use; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt/genetics; Proto-Oncogene Proteins c-akt/metabolism; RNA, Small Interfering/pharmacology; Transcriptional Activation; Tumor Cells, Cultured; Twist Transcription Factor/antagonists & inhibitors; Twist Transcription Factor/metabolism; Twist Transcription Factor/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TWST1

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001158)

Seeded From UniProt

complete

HUMAN:AKT2

involved_in

GO:2000147: positive regulation of cell motility

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TWST1

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TWST1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TWST1

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TWST1

involved_in

GO:2000147: positive regulation of cell motility

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TWST1

involved_in

GO:2000144: positive regulation of DNA-templated transcription, initiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TWST1

GO:2000144: positive regulation of DNA-dependent transcription, initiation

ECO:0000314:

P

According to Figure 3A, the TWIST protein binds to and transactivates the AKT2 promoter, leading to doasage-dependent increase in AKT2.

complete
CACAO 7152

HUMAN:Q05BV0

involved_in

GO:2000147: positive regulation of cell motility

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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