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

Abstract

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/Twistxenografted 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. (Cancer Res 2005; 65(23): 10801-9)

The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis

“…During early embryonic development, TWIST is required for mesoderm induction [6]. In the process of metastasis, TWIST represses E-cadherin and β-catenin expression, promotes EMT, cell motility and invasiveness, and permits the intravasation of tumor cells [3,[7][8][9]. TWIST also enhances AKT2 expression, inhib-its p53 function and cell apoptosis, mediates HIF-1α-enhanced cancer progression, promotes cell survival, and contributes to oncogenesis, angiogenesis and acquired Taxol resistance [7,[10][11][12][13][14].…”

“…In the process of metastasis, TWIST represses E-cadherin and β-catenin expression, promotes EMT, cell motility and invasiveness, and permits the intravasation of tumor cells [3,[7][8][9]. TWIST also enhances AKT2 expression, inhib-its p53 function and cell apoptosis, mediates HIF-1α-enhanced cancer progression, promotes cell survival, and contributes to oncogenesis, angiogenesis and acquired Taxol resistance [7,[10][11][12][13][14]. In agreement with these critical roles in cancer cells, TWIST is overexpressed in breast, gastric, hepatocellular, prostate and bladder cancers, and its upregulation correlates with low E-cadherin expression, high cancer aggressiveness and poor survival rate [3,8,[15][16][17][18][19].…”

PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage

“…Elevated Twist-1 expression is correlated with a poor prognosis and high risk of metastasis in breast, prostate, ovarian, cervical and many others human cancers (Elias et al, 2005;Kwok et al, 2005;Mironchik et al, 2005;Kyo et al, 2006;Puisieux et al, 2006;Hosono et al, 2007;Shibata et al, 2008). Recent reports suggest that high levels of Twist-1 confer cancer cells resistance to various chemotherapeutic drugs (Pham et al, 2007;Zhang et al, 2007;Shiota et al, 2008).…”

Anti‐apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells

“…[4][5][6] Recently, TWIST has been suggested to play a positive role in the development and progression of human cancer. For example, over expression of TWIST is reported in human rhabdomyosarcoma, 7 gastric carcinoma, 8 melonoma, 9 breast cancer, [10][11][12][13] prostate cancer 14 and glioma. 15 In addition, increased TWIST expression levels are associated with advance tumour stage and poor prognosis in several types of cancer.…”