Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer

Abstract

Elevated expression of the integrin-linked kinase (ILK) has been observed in a variety of cancers and has been further correlated with poor clinical outcome. Here, we show that mammary epithelial disruption of ILK results in a profound block in mammary tumor induction. Consistent with these observations, inhibition of ILK function in ErbB2-expressing cells with small molecule inhibitor or RNA interference resulted in profound block in their in vitro invasive properties due to the induction of apoptotic cell death. The rare ILK-deficient tumors that eventually arose overcame this block in tumor induction by an upregulation of ErB3 phosphorylation. These observations provide direct evidence that ILK has a critical role in the initiation phase of ErbB2 tumor induction.

Integrin signalling adaptors: not only figurants in the cancer story

“…Moreover, targeted ablation of ILK in the mammary gland provides a direct demonstration that this molecule is required in the initiation phase of ERBB2-induced tumours, resulting in delayed tumour growth in vivo and a profound block of invasive properties in vitro due to the induction of apoptotic cell death 34 . Recently, it has been described that transgenic MMTV-Wnt/ILK mice show lobuloalveolar hyperplasia and significant acceleration in mammary tumour incidence and growth 35 (Table II).…”

Integrin-linked kinase: Not so ‘pseudo’ after all

“…The onset of ErbB2-dependent tumors is markedly delayed when ILK is deleted in pre-malignant epithelial cells. Inhibition of ILK activity using a small-molecule inhibitor (or siRNA-mediated deletion) suppresses the invasive properties of ErbB2-expressing mammary epithelial cells in vitro, suggesting a role for ILK kinase activity in ErbB2-induced mammary tumor development and progression (Pontier et al, 2010). Alternatively, a small-molecule ILK inhibitor and an ILK-specific siRNA show identical off-target profiles in the mammary epithelium.…”

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

“…Conversely, ILK inhibition suppresses the proliferation and invasive activity of cancer cells (Yau et al, 2005;Troussard et al, 2006). Further, data from mouse models in which ILK is overexpressed (White et al, 2001) or ablated (Pontier et al, 2010) in mammary gland epithelium have demonstrated that ILK functions in tumor growth and metastasis. ILK overexpression and deregulation are frequently observed in a wide variety of human cancers, further implicating ILK in tumorigenesis and cancer progression (Yoganathan et al, 2000;McDonald et al, 2008).…”