Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer.
Aggressive cancer phenotypes are a manifestation of many different genetic alterations that promote rapid proliferation and metastasis. In this study, we show that stable overexpression of Twist in a breast cancer cell line, MCF-7, altered its morphology to a fibroblastic-like phenotype, which exhibited protein markers representative of a mesenchymal transformation. In addition, it was observed that MCF-7/Twist cells had increased vascular endothelial growth factor (VEGF) synthesis when compared with empty vector control cells. The functional changes induced by VEGF in vivo were analyzed by functional magnetic resonance imaging (MRI) of MCF-7/Twist-xenografted tumors. MRI showed that MCF-7/Twist tumors exhibited higher vascular volume and vascular permeability in vivo than the MCF-7/vector control xenografts. Moreover, elevated expression of Twist in breast tumor samples obtained from patients correlated strongly with high-grade invasive carcinomas and with chromosome instability, particularly gains of chromosomes 1 and 7. Taken together, these results show that Twist overexpression in breast cancer cells can induce angiogenesis, correlates with chromosomal instability, and promotes an epithelial-mesenchymal-like transition that is pivotal for the transformation into an aggressive breast cancer phenotype.
Mironchik
Yelena
Y
Department of Radiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
Winnard
Paul T
PT
Vesuna
Farhad
F
Kato
Yoshinori
Y
Wildes
Flonne
F
Pathak
Arvind P
AP
Kominsky
Scott
S
Artemov
Dmitri
D
Bhujwalla
Zaver
Z
Van Diest
Paul
P
Burger
Horst
H
Glackin
Carlotta
C
Raman
Venu
V
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D043171:Chromosomal Instability; D057167:Claudins; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis*; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D051879:Twist-Related Protein 1 / Q000096:biosynthesis*
C473255:CLDN7 protein, human; D057167:Claudins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1