Expression of membrane type-1 matrix metalloproteinase, MT1-MMP in human breast cancer and its impact on invasiveness of breast cancer cells

Jiang, Wen Guo; Davies, Gaynor; Martin, Tracey Amanda; Parr, Christian; Watkins, Gareth; Mason, Malcolm David; Mansel, Robert Edward

doi:10.3892/ijmm.17.4.583

Cited by 84 publications

(121 citation statements)

References 26 publications

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“…The lack of mature invadopodia in Endo II KD cells may be due to defects in MT1-MMP internalization and subsequent trafficking in the absence of Endo II. Consistent with role of invadopodia in promoting tumor progression and metastasis in TNBC (23,41), we also show that Endo II promotes metastasis in TNBC tumor xenograft models. Lastly, we identify a link between elevated Endo II expression and an increased risk of relapse in basal-like breast cancer patients.…”

Section: Discussionsupporting

confidence: 67%

Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

Baldassarre

Watt

Truesdell

et al. 2015

Molecular Cancer Research

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Triple-negative breast cancers (TNBCs) are highly aggressive cancers that lack targeted therapies. However, EGFR is frequently activated in a subset of TNBCs and represents a viable clinical target. Because the endocytic adaptor protein Endophilin A2 (SH3GL1/Endo II) has been implicated in EGFR internalization, we investigated Endo II expression and function in human TNBCs. Endo II expression was high in several TNBC cells compared with normal breast epithelial cells. Stable knockdown (KD) of Endo II was achieved in two TNBC cell lines, and although cell viability was unaffected, defects in receptor-mediated endocytosis were observed. EGFR signaling to Erk and Akt kinases was impaired in Endo II KD cells, and this correlated with reduced rates of EGFR internalization and cell motility. Endo II KD cells also displayed defects in three dimensional (3D) cell invasion, and this correlated with impaired extracellular matrix degradation and internalization of MT1-MMP. Endo II silencing also caused a significant reduction in TNBC tumor growth and lung metastasis in mammary orthotopic tumor xenograft assays. In human breast tumor specimens, Endo II expression was highest in TNBC tumors compared with other subtypes, and at the level of gene expression, high Endo II was associated with reduced relapse-free survival in patients with basal-like breast cancers. Together, these results identify a positive role for Endo II in TNBC tumor metastasis and a potential link with poor prognosis.Implications: Endophilin A2 and related adaptor proteins represent important signaling hubs to target in metastatic cancers. Mol Cancer Res; 13(6); 1044-55. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 67%

Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

Baldassarre

Watt

Truesdell

et al. 2015

Molecular Cancer Research

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“…In previous studies, we implicated the exocyst complex in MT1-MMP trafficking to invadopodia in MDA-MB-231 breast-tumor cells (15) and identified a coordinated function of the exocyst complex and aPKCζ/ι in migrating cells (19). MT1-MMP and aPKCι are overexpressed in various cancers, including breast cancers, and up-regulation is associated with poor prognosis (8,9,22,24). These data suggested the possible interplay between MT1-MMP and aPKCζ/ι in the invasive program of breast-tumor cells.…”

Section: Co-up-regulation Of Mt1-mmp and Apkcι Mrnas Is Associated Withmentioning

confidence: 99%

“…Membrane type 1-matrix metalloproteinase (MT1-MMP) is up-regulated in human cancers, including breast cancers, and it is enriched at the front of invasive lesions (8,9). In tumor-derived cells cultured on a flat ECM substratum, such as gelatin or type I collagen, MT1-MMP accumulates in specialized matrix-degrading plasma-membrane domains called invadopodia (10).…”

mentioning

confidence: 99%

Control of MT1-MMP transport by atypical PKC during breast-cancer progression

Rossé

Lodillinsky

Fuhrmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Dissemination of carcinoma cells requires the pericellular degradation of the extracellular matrix, which is mediated by membrane type 1-matrix metalloproteinase (MT1-MMP). In this article, we report a co-up-regulation and colocalization of MT1-MMP and atypical protein kinase C iota (aPKCι) in hormone receptor-negative breast tumors in association with a higher risk of metastasis. Silencing of aPKC in invasive breast-tumor cell lines impaired the delivery of MT1-MMP from late endocytic storage compartments to the surface and inhibited matrix degradation and invasion. We provide evidence that aPKCι, in association with MT1-MMP-containing endosomes, phosphorylates cortactin, which is present in F-actin-rich puncta on MT1-MMP-positive endosomes and regulates cortactin association with the membrane scission protein dynamin-2. Thus, cell line-based observations and clinical data reveal the concerted activity of aPKC, cortactin, and dynamin-2, which control the trafficking of MT1-MMP from late endosome to the plasma membrane and play an important role in the invasive potential of breast-cancer cells.membrane traffic | actin cytoskeleton | multi-vesicular body | MMP14

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“…The ribozymes were synthesized and cloned into a pEF6/V5-His-TOPO plasmid vector (Invitrogen, Paisley, UK). An appropriate ribozyme transgene and empty pEF6 control plasmid were transfected into HaCaT cells, as previously reported (22,23). Following transfection and blasticidin selection, cells were subsequently cultured in maintenance medium and routinely tested to confirm knockdown of HuR expression.…”

Section: Generation Of Hur Knockdown In Human Keratinocyte Cell Linesmentioning

confidence: 99%

Role of HuR in keratinocyte migration and wound healing

Bosanquet

Harding

et al. 2011

Mol Med Report

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Abstract. Human antigen R (HuR) is a post-translational modifier of mRNAs rich in AU-and U-rich elements. These mRNAs typically code for proteins involved in cell growth and differentiation, signal transduction, transcriptional and translational control, apoptosis, nutrient transport and metabolism. Thus, HuR affects a variety of biological functions and processes. Via its effect on growth and cellular migration, HuR has been shown to enhance clinical progression of a number of cancers. Its role in wound healing remains unknown. In the present study, we evaluated HuR tissue expression in a cohort of chronic healed and non-healed leg ulcers. We also evaluated the effect of HuR knockdown on a number of cellular processes using the HaCaT human keratinocyte cell line. HuR was expressed in greater levels in the 'chronic healed' cohort of ulcers, compared to the 'chronic non-healed', although this failed to reach statistical significance (p= 0.13). HuR knockdown resulted in greater cellular growth, faster progression through the cell cycle and reduced apoptosis. Furthermore, it reduced cellular adhesion rates without affecting migration. We, therefore, concluded that HuR promotes wound healing, primarily through its effect on cellular adhesion. It also slows cellular growth rate via its effect on both cell cycle progression and rates of apoptosis.

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Expression of membrane type-1 matrix metalloproteinase, MT1-MMP in human breast cancer and its impact on invasiveness of breast cancer cells

Cited by 84 publications

References 26 publications

Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

Control of MT1-MMP transport by atypical PKC during breast-cancer progression

Role of HuR in keratinocyte migration and wound healing

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