S100A4 overexpression proves to be independent marker for breast cancer progression

Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia (USM), Penang, Malaysia.
Cancer Cell International (Impact Factor: 2.77). 10/2008; 8(1):12. DOI: 10.1186/1475-2867-8-12
Source: PubMed


Breast cancer is the most common cancer and cause of deaths in women around the world. Oncogene amplification usually occurs late in tumor progression and correlates well with aggressiveness of tumor. In fact the function of the S100A4 protein and its role in metastasis is unclear at present. The purpose of the study was to determine the expression of S100A4 protein in the invasion status and metastatic potential of breast cancer by using tissue microarray and to determine its role in breast cancer based on the expression of S100A4 gene product.
S100A4 protein expression was examined by immunohistochemistry (IHC) using commercially available tissue microarray containing malignant and normal breast tissue cores from 216 patients.
S100A4 was absent in normal breast tissues while positive in 45.1% of infiltrating ductal carcinoma (IDC) node negative and 48.8% of infiltrating lobular carcinoma node negative. In paired samples, S100A4 protein was expressed in 13.5% of IDC node positive cases and 35.1% of matched lymph node metastasis.
S100A4 protein expression appears widely expressed in early and advanced breast cancer stages compared with normal breast. Our study suggests S100A4 may play a role in breast cancer progression and may prove to be an independent marker of breast cancer which appears to be down regulated in more advanced stages of breast cancer.

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    • "One important protein involved in this crosstalk is S100A4. S100A4 is a member of the Ca2+-binding protein S100 family, which has been widely found to be over-expressed in highly metastastic cancers and characterized as a marker of tumour progression [1], [2]. S100A4 is reputed to act both in the intracellular and extracellular environment. "
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    ABSTRACT: The importance of S100A4, a Ca-binding protein, in mediating tumour cell migration, both intracellularly and extracellularly, is well documented. Tissue transglutaminase (TG2) a Ca-dependent protein crosslinking enzyme, has also been shown to enhance cell migration. Here by using the well characterised non-metastatic rat mammary R37 cells (transfected with empty vector) and highly metastatic KP1 cells (R37 cells transfected with S100A4), we demonstrate that inhibition of TG2 either by TG2 inhibitors or transfection of cells with TG2 shRNA block S100A4-accelerated cell migration in the KP1cells and in R37 cells treated with exogenous S100A4. Cell migration was also blocked by the treatment with the non-cell permeabilizing TG2 inhibitor R294, in the human breast cancer cell line MDA-MB-231 (Clone 16, which has a high level of TG2 expression). Inhibition was paralleled by a decrease in S100A4 polymer formation. co-immunoprecipitation and Far Western blotting assays and cross-linking assays showed not only the direct interaction between TG2 and S100A4, but also confirmed S100A4 as a substrate for TG2. Using specific functional blocking antibodies, a targeting peptide and a recombinant protein as a competitive treatment, we revealed the involvement of syndecan-4 and α5β1 integrin co-signalling pathways linked by activation of PKCα in this TG2 and S100A4-mediated cell migration. We propose a mechanism for TG2-regulated S100A4-related mediated cell migration, which is dependent on TG2 crosslinking.
    PLoS ONE 03/2013; 8(3):e57017. DOI:10.1371/journal.pone.0057017 · 3.23 Impact Factor
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    • "Over 80% of patients with osteosarcoma treated with excision alone develop pulmonary metastases, suggesting that the majority of patients with this disease harbor " micrometastases " at diagnosis. There are no histologic or molecular variables which can predict the presence or absence of micrometastasis, and no therapeutic target in OS (Bjørnland et al., 2005).Thus, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of OS.S100A4 (also known as Mts1, metastasin, p9Ka, pEL98, CAPL, calvasculin, Fsp-1, placental calcium-binding protein) belongs to the family of EF-hand calcium-binding proteins, whose expression is elevated in a number of pathological conditions (Ismail et al., 2008; Mencia et al., 2010; Huang et al., 2011; Lo et al., 2011). Although it is well documented that S100A4 is expressed in cancer cells and contributes to tumor cell motility and metastatic progression, the exact underlying mechanisms remain elusive (Berge et al., 2010; Tarabykina et al., 2010). "
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    ABSTRACT: Osteosarcoma (OS), the most frequent bone tumor in children and adolescents, is highly malignant. Metastases are the major cause of death, and patients with relapse have a poor prognosis. Given the associations of S100A4 with OS and tumor metastasis, we explored its potential roles in OS metastasis. Among 32 OS (16 metastatic and 16 non- metastatic) specimens examined, we found a significant increase of S100A4 mRNA in metastatic tissues, and more importantly, expression of S100A4 and MMP-9 to be strongly correlated in patients who had lymph node or distant metastasis. We observed that siRNA mediated suppression of the S100A4 gene significantly reduced the proliferative and invasive capability of highly invasive OS cells, with a reduced rate of tumor growth and metastasis under in vivo conditions. Matrix metalloproteinase 9 (MMP-9) proved highly responsive to S100A4 gene suppression, demonstrating significant reduction in proteolytic activity, while overexpression of S100A4 increased the expression and proteolytic activity of MMP-9. Links of S100A4 with cell motility were confirmed by depletion which resulted in reduced cell migration. Moreover, loss of cell metastatic potential was completely rescued by overexpression of MMP-9. Collectively, our findings indicate that S100A4 contributes to OS metastasis by stimulating MMP-9 expression, suggesting potential as a novel diagnostic biomarker for OS progression as well as a therapeutic target.
    Asian Pacific journal of cancer prevention: APJCP 01/2011; 12(8):2075-80. · 2.51 Impact Factor
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    • "Since the anatomy of the human and mouse mammary glands differ, we also looked at S100A4 immunostaining in normal mouse mammary gland, with similar outcome (Supplementary Fig. 3). Expression of S100A4 in early stage breast carcinoma cells has been reported as an independent marker of poor prognosis (Ismail et al., 2008; Lee et al., 2004; Rudland et al., 2000). "
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    ABSTRACT: 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 S100A4 induced a 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, in concert with TGFα by activating MMP-3, and 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.
    Developmental Biology 12/2010; 352(2):181-90. DOI:10.1016/j.ydbio.2010.12.033 · 3.55 Impact Factor
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