MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

Abstract

As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic capabilities, invading tumor cells must acquire the capacity to negotiate this novel microenvironment. Collagen influences the fate of epithelial cells by inducing apoptosis. However, the mechanisms used by invading tumor cells to evade collagen-induced apoptosis remain to be defined. We demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) confers breast cancer cells with the ability to escape apoptosis when embedded in a collagen gel and after orthotopic implantation in vivo. In the absence of MMP-14-dependent proteolysis, type I collagen triggers apoptosis by inducing the expression of the pro-apoptotic Bcl-2-interacting killer in luminallike breast cancer cells. These findings reveal a new mechanism whereby MMP-14 activity promotes tumor progression by circumventing apoptosis.

ADAM12 redistributes and activates MMP-14, resulting in gelatin degradation, reduced apoptosis, and increased tumor growth

“…1E), and adding doxycycline to the growth medium switched off ADAM12 expression (MCF7-A12Dcyt+dox). In contrast to earlier publications (Deryugina et al, 2000;Figueira et al, 2009;Maquoi et al, 2012), we were able to detect equal levels of MMP-14 under all three experimental conditions (Fig. 1E).…”

“…MMP-14 is a classical transmembrane metalloproteinase and, like ADAM12, it is upregulated in human cancer (Egeblad and Werb, 2002;Figueira et al, 2009;Jiang et al, 2006;Seiki, 2003;Strongin, 2010) and accelerates tumor progression in mouse models of cancer (Fröhlich et al, 2011;Kveiborg et al, 2005;Maquoi et al, 2012;Perentes et al, 2011;Roy et al, 2011). MMP-14 degrades extracellular matrix components (i.e.…”

“…MMP-14 degrades extracellular matrix components (i.e. fibrillar collagen and gelatin), activates enzymes such as MMP-2 and MMP-13, sheds cell surface proteins (Chan et al, 2012;Egeblad and Werb, 2002;Itoh and Seiki, 2006;Koshikawa et al, 2011;Koshikawa et al, 2010), and was recently shown to prevent collagen-induced apoptosis (Maquoi et al, 2012). The activity of MMP-14 is regulated by multiple mechanisms, including activation by cell surface proteins such as tetraspanin CD151 and aVb3 integrins (Deryugina et al, 2004;Gonzalo et al, 2010;Hadler-Olsen et al, 2011;Itoh and Seiki, 2004;Yañez-Mó et al, 2008).…”

Vinculin negatively regulates transcription of MT1-MMP through MEK/ERK pathway

“…Recent studies have demonstrated that MT1-MMP protects cancer cells from apoptosis induced by collagen gel culture [21]. HSC-4 cells used here express mutant form of p53-R248Q [22] and lack the expression of PTEN (Fig.…”

Effects of Matrix Metalloproteinase on Tumour Growth and Morphology via Haptotaxis

“…MT1-MMP (MMP14) has emerged as an important collagenase that cancer cells use to degrade and invade in a collagen-rich environment [9,10]. While poorly invasive breast adenocarcinoma cells undergo apoptosis when confronted with a collagen-rich environment, the production of MT1-MMP endows these cells with the capacity to escape from collagen-induced apoptosis [11]. The localized activity of MT1-MMP helps tumour cells to overcome higher collagen density found in some peritumoural stroma [12].…”