Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer.
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of intracellular signaling by integrins, a major family of cell surface receptors for extracellular matrix, in the regulation of different cellular functions in a variety of cells. Upon activation by integrins through disruption of an autoinhibitory mechanism, FAK undergoes autophosphorylation and forms a complex with Src and other cellular proteins to trigger downstream signaling through its kinase activity or scaffolding function. A number of integrins are identified as surface markers for mammary stem cells (MaSCs), and both integrins and FAK are found to play crucial roles in the maintenance of MaSCs in studies using mouse models, suggesting that integrin signaling through FAK may serve as a functional marker for MaSCs. Consistent with previous studies linking increased expression and activation of FAK to human breast cancer, these findings suggest a novel cellular mechanism of FAK promotion of mammary tumorigenesis by maintaining the pools of MaSCs as targets of oncogenic transformation. Furthermore, FAK inactivation in mouse models of breast cancer also reduced the pool of mammary cancer stem cells (MaCSCs), decreased their self-renewal in vitro, and compromised their tumorigenicity and maintenance in vivo, suggesting a potential role of integrin signaling through FAK in breast cancer growth and progression through its functions in MaCSCs. This review discusses these recent advances and future studies into the mechanism of integrin signaling through FAK in breast cancer through regulation of MaCSCs that may lead to development of novel therapies for this deadly disease.
Guan
Jun-Lin
JL
Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. jlguan@umich.edu
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*
D016023:Integrins; D011506:Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases