p53-Dependent repression of focal adhesion kinase in response to estradiol in breast cancer cell-lines.
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.
International Agency for Research on Cancer, Lyon, France.
Suresh
S
Anaganti
Lynnette
L
Fernández-Cuesta
Anita
A
Langerød
Pierre
P
Hainaut
Magali
M
Olivier
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D051417:Focal Adhesion Kinase 1