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Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival.

ABSTRACT: PURPOSE:MMP9 is a matricellular protein associated with extracellular matrix (ECM) remodelling, that promotes tumour progression, and modulates the activity of cell adhesion molecules and cytokines. This study aims to assess the prognostic value of MMP9 and its association with cytoskeletal modulators in early-stage invasive breast cancer (BC). METHODS:MMP9 expression was evaluated by immunohistochemistry using a well-characterised series of primary BC patients with long-term clinical follow-up. Association with clinicopathological factors, patient outcome and ECM remodelling BC-biomarkers were investigated. METABRIC dataset, BC-GenExMiner v4.0 and TCGA were used for the external validation of MMP9 expression. GSEA gene enrichment analyses were used to evaluate MMP9 associated pathways. RESULTS:MMP9 immunopositivity was observed in the stroma and cytoplasm of BC cells. Elevated MMP9 protein levels were associated with high tumour grade, high Nottingham Prognostic Index, and hormonal receptor negativity. Elevated MMP9 protein expression correlated significantly with cytokeratin 17 (Ck17), Epidermal Growth Factor Receptor (EGFR), proliferation (Ki67) biomarkers, cell surface adhesion receptor (CD44) and cell division control protein 42 (CDC42). Cytoplasmic MMP9 expression was an independent prognostic factor associated with shorter BC-specific survival. In the external validation cohorts, MMP9 expression was also associated with poor patients' outcome. Transcriptomic analysis confirmed a positive association between MMP9 and ECM remodelling biomarkers. GSEA analysis supports MMP9 association with ECM and cytoskeletal pathways. CONCLUSION:This study provides evidence for the prognostic value of MMP9 in BC. Further functional studies to decipher the role of MMP9 and its association with cytoskeletal modulators in BC progression are warranted.

SUBMITTER: Joseph C

PROVIDER: S-EPMC7297818 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival.

Joseph Chitra C Alsaleem Mansour M Orah Nnamdi N Narasimha Pavan L PL Miligy Islam M IM Kurozumi Sasagu S Ellis Ian O IO Mongan Nigel P NP Green Andrew R AR Rakha Emad A EA

Breast cancer research and treatment 20200522 2

<h4>Purpose</h4>MMP9 is a matricellular protein associated with extracellular matrix (ECM) remodelling, that promotes tumour progression, and modulates the activity of cell adhesion molecules and cytokines. This study aims to assess the prognostic value of MMP9 and its association with cytoskeletal modulators in early-stage invasive breast cancer (BC).<h4>Methods</h4>MMP9 expression was evaluated by immunohistochemistry using a well-characterised series of primary BC patients with long-term clin ...[more]

PMID: 32445177

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Project description:IntroductionSyntenin is a scaffolding-PDZ domain-containing protein. Although it is reported that syntenin is associated with melanoma growth and metastasis, the possible role of syntenin in breast cancer has not been well elucidated. The present study investigated the expression and function of syntenin in breast cancer.MethodsReal-time polymerase chain reaction (PCR) and Western blots were used to determine the mRNA and protein expression of syntenin. With a combination of overexpression and RNA interference, the effect of syntenin on migration, invasion, and ERK1/2 activation was examined in breast cancer cell lines. The effect of syntenin in vivo was assessed with an orthotropic xenograft tumor model in BALB/c nu/nu mice. In addition, the expression level of syntenin in clinical breast cancer tissues was evaluated with immunohistochemistry. The Kaplan-Meier survival curve was used to evaluate patient survival, and the Cox proportional hazards model was used for multivariate analysis.ResultsOur study showed that syntenin expression was upregulated in high-metastasis breast cancer cell lines and breast cancer tissues. Overexpression of syntenin in breast cancer cells promoted cell migration and invasion in vitro. Moreover, overexpression of syntenin promoted breast tumor growth and lung metastasis in vivo. We further showed that activation of integrin ?1 and ERK1/2 was required for syntenin-mediated migration and invasion of breast cancer cells. The correlation between syntenin expression and tumor size (P = 0.011), lymph node status (P = 0.001), and recurrence (P = 0.002) was statistically significant. More important, syntenin expression in primary tumors was significantly related to patients' overall survival (OS; P = 0.023) and disease-free survival (DFS; P = 0.001). Its status was an independent prognostic factor of OS (P = 0.049) and DFS (P = 0.002) in our cohort of patients.ConclusionsThese results suggest that syntenin plays a significant role in breast cancer progression, and it warrants further investigation as a candidate molecular marker of breast cancer metastasis and a potential therapeutic target.

Project description:A-kinase-interacting protein 1 (AKIP1), as a recently discovered oncoprotein, promotes cell malignant behaviors in gynecological malignancies. To the best of our knowledge, no study reports its clinical value in patients with endometrial carcinoma. The present study aimed to explore the association between AKIP1 expression and clinical features and survival in patients with endometrial carcinoma, and to assess the effect of AKIP1 knockdown on the regulation of chemosensitivity in vitro. The tumor and adjacent tissue specimens from 101 patients with endometrial carcinoma were retrieved for AKIP1 protein expression analysis using an immunohistochemistry (IHC) assay. Meanwhile, specimens from 54 patients with endometrial carcinoma were analyzed for AKIP1 mRNA expression using reverse transcription-quantitative PCR. Furthermore, an in vitro experiment was conducted in the Ishikawa cell line to determine the effect of AKIP1 modification on the chemosensitivity of cisplatin and paclitaxel. AKIP1 IHC score (P<0.001) and mRNA expression levels (P<0.001) were increased in tumor tissues compared with those in adjacent tissues. Moreover, increased AKIP1 IHC score was associated with lymphovascular invasion (P=0.007), advanced International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.002) and shorter overall survival (OS) time (P=0.035) in the patients with endometrial carcinoma. Meanwhile, upregulated AKIP1 mRNA expression levels were associated with lymphovascular invasion (P=0.020) and advanced FIGO stage (P=0.027) in the patients with endometrial carcinoma. Multivariate Cox regression showed that tumor AKIP1 protein expression (high vs. low) independently predicted a shorter OS time (P=0.036). Silencing of AKIP1 decreased Ishikawa cell viability when treated with 5, 10, 20 and 40 µM cisplatin (all P<0.05) and decreased the half maximal inhibitory concentration value of cisplatin (P=0.003), whereas its effect on paclitaxel chemosensitivity was less obvious. Overall, elevated AKIP1 expression was associated with tumor invasion, shorter survival time and decreased chemosensitivity in endometrial carcinoma.

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Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival.

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Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival.

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