Mechanisms of Twist 1-Induced Invasion in Breast Cancer Metastasis
Annual summay rept. 1 Jan 2010-31 Dec 2010
CALIFORNIA UNIV SAN DIEGO LA JOLLA
Pagination or Media Count:
Here we identify a novel role for PDGFR-alpha as an essential downstream target of the transcription factor Twist1 for metastasis and local invasion. Twist1 induces the formation of structures called invadopodia that concentrate protease activity to areas of the cell in contact with the extracellular matrix. Twist1-induced invasion and metastasis are dependent on invadopodia formation, as knockdown of an essential invadopodia protein, Tks5, reduces invasion and metastasis. Twist1 induces invadopodia formation by directly inducing transcription of the tyrosine kinase receptor PDGFR-alpha. Upregulation of PDGFR-alpha is necessary for an increase in Src activation observed upon expression of Twist1 in human mammary epithelial cells. Knockdown of PDGFR-alpha reduces both in vitro and in vivo invasion and metastasis. In addition, we identify Twist1 and PDGFR-alpha as markers of poor survival in breast cancer patient populations.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research