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Twist Overexpression Induces In vivo Angiogenesis and Correlates with Chromosomal Instability in Breast Cancer

Departments of ¹ Radiology and ² Orthopedic Surgery, Johns Hopkins University, School of Medicine, Baltimore, Maryland; ³ Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands; ⁴ Institute of Pathology, University of Munster, Munster, Germany; and ⁵ Division of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, California

Requests for reprints: Venu Raman, Department of Radiology, Johns Hopkins University School of Medicine, 340 Traylor Building, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-955-7492; Fax: 410-614-1948; E-mail: vraman2{at}jhmi.edu.

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.

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