Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling

Giancotti, F. G., et al. 2009. J. Clin. Invest. 119(2):252-66.

Speaker: Yu-Fen Tseng (曾鈺芬)                                    Time: 13:10~14:00, Apr. 29, 2009

Commentator: Dr. Bei-Chang Yang (楊倍昌老師) Place: Room 601

Abstract:

Tumor cells need oncogenic signaling to maintain their malignance, such as Ras and PI3K signaling pathways. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase is recruited to focal adhesion and activated through binding to the cytoskeletal proteins, Talin and Paxillin when integrins bind to the extracellular matrix. Autophosphorylation of FAK at Y397 activates PI3K and Ras signalings through binding with Src. FAK plays an important role in cell survival, proliferation, and invasion. Knockdown of FAK inhibits the invasion and metastasis of human breast cancer cells ¹. Whether FAK is required for tumor initiation or progression in the breast is not known.. The authors show that FAK is amplified in 50% of the human breast tumors. They used the mouse mammary tumor virus-polyoma middle T protein (MMTV-PyMT) mice to study breast tumorigenesis. Conditional deletion of FAK in the MMTV-PyMT;Cre;FAK^fl/fl mice was conducted by Cre and loxp technique and which mammary tumorigenesis was inhibited. In the absence of FAK, tumor cell proliferation, invasion, survival ability and metastasis were suppressed. The authors further revealed that autophosphorylation of FAK at Y397 is required for the activation of FAK and tumorigenesis. The authors also show that FAK is required to maintain the transformed phenotype of oncogenes PyMT- and Ras- transformed cells. FAK also cooperates with integrin β4 signaling to sustain Neu-mediated transformation ². FAK silencing does not suppress oncogenic signaling and does not affect normal mammary epithelial cells. FAK function in the human breast cancer cells is consistent with that in mice model. Together, FAK is a necessary component in the oncogenic signaling network which initiates and supports mammary tumorigenesis. FAK appears to be a potential target in oncogenic signaling, and may exhibit broad therapeutic efficacy in breast cancer.

References:

1. McLean, G.W., et al. Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. Genes & development 18, 2998-3003 (2004).

2. Guo, W., et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 126, 489-502 (2006).