Display Settings:

Format

Send to:

Choose Destination
We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Cancer Lett. 2011 Jan 28;300(2):215-24. doi: 10.1016/j.canlet.2010.10.008. Epub 2010 Nov 10.

p53-Dependent repression of focal adhesion kinase in response to estradiol in breast cancer cell-lines.

Author information

  • 1International Agency for Research on Cancer, Lyon, France.

Abstract

Mutations in the TP53 suppressor gene are frequent in breast cancers. These mutations are associated with poor prognosis, thought to be due to proliferative advantage and poor response to chemotherapy associated with loss of p53 function. The focal adhesion kinase (FAK/PTK2), a tyrosine kinase, is over-expressed in a variety of human tumors including breast cancers. FAK is a critical regulator of adhesion and motility and its over-expression is associated with increased metastatic potential. Recently, FAK promoter has been shown to contain p53 responsive elements and to be down-regulated by DNA-damage in a p53-dependent manner. Here, we have used five estrogen-dependent breast cancer cells lines with different p53 status, including an isogenic model, to show that FAK expression was regulated in a p53-dependent manner in response to estradiol. FAK protein and mRNA expression were down-regulated by estradiol in wild-type but not mutant p53 cells. Moreover, silencing wild-type p53 increased FAK expression, while over expressing p53 repressed FAK expression. ChIP experiment showed that p53 bound to FAK promoter in the presence of estradiol in p53 wild-type but not in mutant p53 cells, suggesting a direct role of p53 in down regulating FAK mRNA expression. FAK mRNA expression was also found to correlate with TP53 mutation status in a series of breast tumors. Finally, loss of FAK down-regulation in p53 mutant cells was correlated with increased proliferation and invasion upon estradiol stimulation, while FAK silencing reduced invasion. These results suggest that p53 is an important down regulator of FAK and that loss of p53 function in breast cancer may contribute to the metastatic potential of estrogen-responsive tumors through uncontrolled FAK expression upon estrogens stimulation.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

PMID:
21071137
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Elsevier Science
    Loading ...
    Write to the Help Desk