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Review
. 2010 Apr;62(4):268-76.
doi: 10.1002/iub.303.

Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer

Jun-Lin Guan  1
Affiliations
Review

Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer

Jun-Lin Guan. IUBMB Life. 2010 Apr.

Abstract

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.

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Figures

Fig. 1
Fig. 1. FAK mediated integrin signaling pathways
Integrin-mediated cell adhesion to ECM activates FAK by disruption of an auto-inhibitory interaction of the kinase and amino terminal FERM domain. The activated FAK undergoes autophosphorylation and binds to Src and other intracellular signaling molecules to trigger multiple downstream pathways to regulate different cellular functions such as survival, proliferation, migration and invasion.
Fig. 2
Fig. 2. Inactivation of FAK suppresses breast cancer development and progression caused by deficient self-renewal and decreased pool of MaSCs and MaCSCs in mouse models
In the normal mammary glands, integrin signaling through FAK contributes to the self-renewal of MaSC (light grey), which can be transformed by oncogenes such as PyMT to form MaCSCs (black) with significantly increased self-renewal and tumorigenecity (more circular lines). MaEC-specific deletion of FAK (FAK CKO) results in deficient self-renewal (broken circular lines) and reduced pool of MaSCs. The reduced pool of MaSCs may contribute to the decreased mammary tumorigenesis (i.e. reduced frequency of MaCSCs formation). The FAK-null MaCSCs (dark grey) also exhibit deficient self-renewal and tumorigenecity (broken circular lines). The deficient self-renewal and the reduced pool of MaCSCs could account for the suppressed growth and progression of mammary tumors developed in these mice.
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