S100A4 overexpression proves to be independent marker for breast cancer progression

Ismail, Nawfal; Kaur, Gurjeet; Hashim, Hasnah; Hassan, Mohammed

doi:10.1186/1475-2867-8-12

Cited by 43 publications

(40 citation statements)

References 41 publications

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“…We speculate that by binding to TG2, S100A4 could potentiate integrin-mediated signaling, and thus enhance cell adhesion and migration, leading to increased metastasis in tumors in which both proteins are overexpressed and released to the ECM. Indeed, both TG2 and S100A4 were found to contribute to the high metastatic properties of several cancers, such as breast and colorectal tumors [42][43][44][45]. It cannot be ruled out that TG2 and S100A4 also interact inside tumor cells (as they both have important intracellular functions) or other cell types as well, and either by cross-linking activity of TG2 or additional protein-protein interactions contribute to the pathomechanism of various tumors.…”

Section: Discussionmentioning

confidence: 99%

Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2

Biri

Kiss

Király

et al. 2015

Biochemical Journal

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Transglutaminase-2 (TG2) is best known as a Ca 2+ -dependent cross-linking enzyme; however, some of its extracellular matrix-related functions are independent from its catalytic activity and include matrix remodeling, adhesion and migration. S100A4 belongs to the Ca 2+ -binding EF-hand S100 protein family and acts both intra-and extracellularly through binding to various partners. It regulates cell migration and its overexpression is strongly associated with metastasis and poor survival in various cancers. TG2 has recently been suggested to mediate S100A4-dependent tumor cell migration. Here we provide evidence that S100A4 is an interacting partner and also specific amine donor of TG2. TG2 incorporates a glutamine donor peptide to Lys100 in the C-terminal random coil region of S100A4. Importantly, the enzyme activity is not necessary for the interaction: S100A4 also binds to TG2 in the presence of a specific inhibitor that keeps the enzyme in an open conformation, or to an enzymatically inactive mutant. We also found that S100A4 considerably enhances TG2-mediated adhesion of A431 epithelial carcinoma cells to the extracellular matrix. This role is independent of enzyme activity and requires the open conformation of TG2. We propose that S100A4 stabilizes the open conformation of TG2, which binds to its cell surface receptor in this state and increases cell adhesion.Summary: S100A4 and transglutaminase-2 have a role in metastasis. S100A4 is an interaction partner and specific amine substrate of transglutaminase-2, promoting its open conformation and leading to enhanced cell adhesion. Studying their interaction could contribute to the better understanding of metastasis.Running title: S100A4: substrate and binding partner of transglutaminase-2

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Section: Discussionmentioning

confidence: 99%

Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2

Biri

Kiss

Király

et al. 2015

Biochemical Journal

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“…S100A4 belongs to the S100 calcium binding protein family and may be characterized as a cytoplasmic protein that promotes cellular motility via direct interaction with myosin-IIA and also has functions in cell cycle progression. Its overexpression has been documented in breast (9)(10)(11)(12), gastric (13), colorectal (14)(15)(16), esophageal squamous cell (17) and gallbladder carcinoma (18), ovarian (19) and bladder cancer (20), papillary thyroid carcinoma (21,22) and non-small cell lung cancer (23). In addition, its upregulation has been associated with disease progression, metastasis and decreased patient survival.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of cytoplasmic expression of S100A4 protein in endometrial carcinoma

et al. 2014

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Abstract. The S100A4 protein, a member of the S100 family of calcium-binding proteins, has been considered as a candidate prognostic marker in patients with cancer. The present study was conducted to evaluate the prognostic value of S100A4 and to examine its correlation with the clinicopathological parameters and the overall survival and progression-free survival in patients with endometrial carcinoma (EC). To do this, we performed immunohistochemistry of formalin-fixed tissue sections obtained from 135 cases of EC. In addition, we quantified the level of S100A4 mRNA using the quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). The cytoplasmic expression of S100A4 protein was observed in 35 cases (25.9%). There was a significant association between the expression of S100A4 and clinicopathological parameters such as histologic grade, FIGO stage, lymph node metastasis and loss of progesterone receptor (PR). qRT-PCR demonstrated that the level of S100A4 mRNA was significantly higher in ECs as compared with normal endometrium. The cytoplasmic expression of S100A4 had a significant correlation with shorter overall survival and progression-free survival on the Kaplan-Meyer survival analysis. In multivariate analysis, there was a significant correlation between S100A4 expression and a poorer OS. In conclusion, our results indicate that S100A4 may be a biological marker indicating the recurrence and poor prognosis in patients with EC.

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“…Additionally, S100A4 was one of only 25 genes found upregulated in three different mammary cancer stem cell expression signatures (Gupta et al, 2009). Numerous other reports on clinical material from breast (Ismail et al, 2008;Lee et al, 2004), bladder (Matsumoto et al, 2007), colorectal (Flatmark et al, 2003;Gongoll et al, 2002), melanoma and several other types of cancer (Garrett et al, 2006) have confirmed the association between S100A4 expression, and a more severe prognosis. Collectively these findings suggest S100A4 as a major determinant of breast cancer progression.…”

mentioning

confidence: 56%

“…The link between expression of S100A4 in breast carcinoma cells, and poor patient outcome, has been soundly established (Ismail et al, 2008;Lee et al, 2004;Rudland et al, 2000). Since very few studies have looked at the expression and function of this protein in nonmalignant cells and tissue, the aim for the present work was to elucidate the biological function of S100A4 in normal mammary gland.…”

Section: Discussionmentioning

confidence: 99%

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

Andersen¹,

Mori²,

Fata³

et al. 2010

European Journal of Cancer Supplements

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High levels of the S100 calcium binding protein S100A4 also called fibroblast specific protein 1 (FSP1) have been established as an inducer of metastasis and indicator of poor prognosis in breast cancer. The mechanism by which S100A4 leads to increased cancer aggressiveness has yet to be established; moreover, the function of this protein in normal mammary gland biology has not been investigated. To address the role of S100A4 in normal mammary gland, its spatial and temporal expression patterns and possible function in branching morphogenesis were investigated. We show that the protein is expressed mainly in cells of the stromal compartment of adult humans, and during active ductal development, in pregnancy and in involution of mouse mammary gland. In 3D culture models, topical addition of S1004 induced significant increase in the TGFα mediated branching phenotype and a concomitant increase in expression of a previously identified branching morphogen, metalloproteinase-3 (MMP-3). These events were found to be dependent on MEK activation. Downregulation of S100A4 using shRNA significantly reduced TGFα induced branching and altered E-cadherin localization. These findings provide evidence that S100A4 is developmentally regulated and that it plays a functional role in mammary gland development by, in concert with TGFα, activating MMP-3, thereby increasing invasion into the fat pad during branching. We suggest that S100A4-mediated effects during branching morphogenesis provide a plausible mechanism for how it may function in breast cancer progression.

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S100A4 overexpression proves to be independent marker for breast cancer progression

Cited by 43 publications

References 41 publications

Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2

Metastasis-associated S100A4 is a specific amine donor and an activity-independent binding partner of transglutaminase-2

Prognostic value of cytoplasmic expression of S100A4 protein in endometrial carcinoma

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

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