MMP-2 In Breast Cancer Research Articles

Association between the Expression of KISS1, KISS1R and MMP-9 in Invasive Breast Carcinomas

Metastases are the leading cause of fatal outcome in patients with breast cancer, therefore different proteins related to metastasis are widely studied for the potential to control the spread of cancer cells. It has been shown in various types of cancers that the anti-metastatic role of the KISS1/KISS1R system has been performed by suppressing metalloproteinase 9 (MMP-9) expression, but there is evidence that the relationship between KISS1/KISS1R signalling and MMP-9 in breast cancer seems to be different. The aim of the current study was to assess the association between protein expression of KISS1, KISS1R and MMP-9 using software-based measurement of staining intensity and the possible link to tumour size, grade and receptor status in invasive breast carcinomas. Standard histopathological parameters were determined by an experienced pathologist and immunohistochemical staining for KISS1, KISS1R and MMP-9 was performed on tissue samples from 54 patients. Evaluation of staining intensity was performed using ImageJ software on RGB images by two operators. Results showed significant strong positive correlation between KISS1, KISS1R and MMP-9 and strong expression of studied proteins in tumour associated stromal cells. No association was found between the expression of the studied proteins and size, receptor status or grade. Higher expression of KISS1R, however, was observed in HER2-negative compared to HER2-positive carcinomas, which might indicate an alternative pathway for stimulating pro- proliferation of tumour cells when HER2 expression is low.

Expression and Clinical Significance of Hypoxia-related Factors HIF-1a, Gli-1 and MMP9 in Breast Cancer

Objective: To investigate the expression and clinical significance of hypoxia inducible factors HIF-1a, Gli-1 and MMP9 in breast cancer. Methods: Eighty patients with invasive ductal carcinoma of the breast and 40 normal tissues adjacent to cancer were selected. Immunohistochemical methods were used to detect the expression of HIF-1a, Gli-1 and MMP9 in breast cancer and normal tissues adjacent to cancer, and their relationship with clinicopathological features of breast cancer and prognosis was explored. Results: The positive rates of HIF-1a, Gli-1 and MMP9 in breast cancer tissues were significantly higher than those in normal breast tissues. HIF-1a, Gli-1 and MMP9 expressions are positively correlated in breast cancer. Conclusion: HIF-1a, Gli-1 and MMP9 proteins are involved in the pathogenesis of breast cancer.

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

PurposeMMP9 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).MethodsMMP9 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.ResultsMMP9 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.ConclusionThis 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.

Meme Kanserinde MMP-2 ve MMP-9'un Rolü

Matriks metalloproteinaz (MMP)lar kalsiyum ve çinko bağımlı proteolitik enzim ailesidir. Bu ailenin bir üyesi olan MMP-2 ve MMP9 jelatini, tip IV, V, VII ve X kollajeni parçalayan tip IV kollajenazlardır. MMP-2 fibroblastlar, endotel hücreleri ve osteoblastlar; MMP-9 inflamatuar hücreler, tümör hücreleri, keratinositler ve epitel hücreleri tarafından sentezlenmektedir. Jelatinazlar, zimojen olarak salgılanırlar ve prodomainlerin bölünmesi ile aktif formlarına dönüşürler. MMP-2 ve MMP-9, meme kanseri hücrelerinde proliferasyon, migrasyon, invazyon ve metastaza yol açmaktadır. Hem MMP-2'nin hem de MMP9'un, meme kanseri tedavisine yönelik olarak polimorfizmlerini ve ekspresyonlarını/aktivitelerini araştıran çalışmalar bulunmaktadır. Meme kanseri progresyonu ve metastazındaki önemli rolleri nedeni ile bu enzimlerin ortak fonksiyonel polimorfizmlerinin, hasta sağkalımını da içeren fenotipik özellikleriyle meme kanseri gelişimine katkıda bulunduğu bildirilmektedir. Di-2-Etilheksilfitalat, PAX6, hücresel prion proteini, natriüretik peptid reseptörü A, aktif lökosit hücre adezyon molekülü, EZH2, eGFR'nin ligand EGF ile etkileşimi, integrin ve integrin olmayan reseptörlerle etkileşim, TF-FVIIa/tripsin aracılı proteaz ile reseptör 2'nin aktivasyonu ile MMP-2 ve/veya MMP-9'un ekspresyonunun arttığı gösterilmektedir. Meme kanserinde invazyon ve metastaz üzerindeki etkileri nedeni ile potansiyel tedavi hedefi olarak MMP-2 ve MMP-9'u inhibe etmeye yönelik olarak Alisol A, Casticin, Orientin, Luteolin ve [15]pyN5 ve [16]pyN5 üzerinde yapılan çalışmalar bulunmaktadır. Bu derlemede, meme kanserinde MMP-2 ve MMP-9'un rolü, polimorfizmleri, bu enzimlerin ekspresyonunu/aktivitesini artıran etkileşimleri, moleküller ile inhibisyonları incelenecek ve son yıllarda yapılan çalışmalar sunulacaktır.

MATRIKs METALOPROTEINASE-2 DI METASTASIS KARSINOMA PAYUDARA

Matrix Metalloproteinase-2 is a family of extra cellular matrix degrading proteinases. Study results on the role of MMP-2 in breast cancer progression and metastasis are still controversial. The aim of this study was to know the MMP-2 level by analyzing in metastatic and non metastatic breast cancer patients by using a cross sectional design, it was carried out in the Wahidin Sudirohusodo, Ibnu Sina, Labuang Baji Hospitals and at the Research Unit of UNHAS Makassar from April 2012 until June 2012. The 56 breast cancer patients were divided into two groups: metastatic and non metastatic based on their thorax photo, ultrasonography and/or bone scan results. They were also divided into early and advanced stage, based on their TNM staging. The matrix metalloproteinase-2 level was determined by ELISA method. The result of this study showed that the mean levels of MMP-2 in metastatic and non metastatic breast cancer were 20.18 ng/mL and 17.14 ng/mL, respectively. The independent sample T test showed there was a significant difference (p=0.018) in MMP-2 levels between metastatic and non metastatic breast cancer. The mean level of MMP-2 in early and advanced stages was 17.10 ng/mL and 18.31 ng/mL, respectively, the independent sample T test showed no significant difference of MMP-2 level between both stages. One way ANOVA test showed no significant difference of MMP-2 level based on tumour size and regional lymph node infiltration. The MMP-2 contributed to the metastasis in breast cancer patients. The matrix metalloproteinase-2 level in metastatic was higher than in the non metastatic breast cancer, so this condition could be used as a biomarker to predict the metastasis of breast cancer.

S100A4 participates in epithelial-mesenchymal transition in breast cancer via targeting MMP2

Numerous studies have shown that S100A4 acquires its metastasis-promoting effects via inducing epithelial-mesenchymal transition (EMT). However, its role and mechanism in EMT in breast cancer had not been clearly elucidated. Herein, we showed that the knockdown of S100A4 expression in breast cancer cell lines, MDA-MB-231 and MDA-MB-468, inhibited not only cell invasion ability greatly, but also the occurrence of EMT significantly. In addition, S100A4 knockdown could also decrease the expression of MMP2, a promoter and a mediator of the EMT processes in cancer. Above all, restoring the expression of MMP2 in MDA-MB-231 and MDA-MB-468 could not only rescue the invasion ability inhibited by knockdown of S100A4, but also reverse the EMT suppressed by knockdown of S100A4. In summary, our results indicated that S100A4 could promote the invasion ability of breast cancer cells via EMT, more importantly, it could participate in EMT via regulating MMP2 in breast cancer. Therefore, S100A4 could be a candidate biomarker for defining breast cancer metastasis and useful target for therapy.

Expression of SM22α and its relationship with lymph node metastasis in breast cancer

to analyze the relationship between the expression of SM22α and the lymph node (LN) metastasis of breast cancer and to investigate its molecular mechanisms. reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect the expression of SM22α in breast cancer tissue and adjacent normal breast tissue. RT-PCR and Western blot were employed to investigate the SM22α mRNA and protein level in tissues of breast fibroadenoma, breast cancer without LN metastasis and breast cancer with LN metastasis. RT-PCR and zymography were used to detect the MMP2 and MMP9 expression and activity and TIMP1 expression level in breast fibroadenoma, breast cancer samples without LN metastasis and those with LN metastasis respectively. the expression level of SM22α mRNA in breast cancer was significantly lower than that in breast fibroadenoma or adjacent normal breast tissue (5.1% ± 2.4% vs 15.1% ± 5.3% vs 30.1% ± 5.1%, P < 0.01). The protein and mRNA expression level of SM22α in breast cancer samples with LN metastasis were significant lower than those of breast cancer without LN metastasis (6.2% ± 3.1% vs 10.1% ± 4.1%, P < 0.01). Both the expression and activity of MMP2 and MMP9 in breast cancer samples with LN metastasis were significant higher than those without LN metastasis (P < 0.01). A strong negative correlation was found between SM22α protein level and MMP2 activity (r = -0.848; n = 27; P < 0.01) or MMP9 activity (r = -0.916; n = 27; P < 0.01) in breast cancer tissue. a down-regulation of SM22α in breast cancer is correlated with LN metastasis. SM22α may inhibit the LN metastasis through a negative regulation of MMP2 and MMP9 in breast cancer.

Concluding remarks

Concluding remarks

Circulating MMP2 and MMP9 in breast cancer—Potential role in classification of patients into low risk, high risk, benign disease and breast cancer categories

Matrix metalloproteinase (MMP) 2 and 9 are involved in cancer invasion and metastasis, and increased levels occur in serum and plasma of breast cancer (BC) patients. It is, however, unclear whether changes in serum levels can be exploited for early detection or classification of patients into different risk/disease categories. In our study, we measured concentration and activity of MMP2/9 in sera of 345 donors classified as low risk (Gail score <1.7), high risk (HR) (Gail score > or =1.7), benign disease or BC. Kruskal-Wallis and Mann-Whitney nonparametric tests showed that total-MMP2 concentration is higher in HR compared to control (p = 0.012), benign (p = 0.001) and cancer (p = 0.007). Active MMP2 (aMMP2) concentration is higher in control than benign and cancer (p < 0.001, respectively). Total and aMMP9 concentrations are higher in cancer than benign (p < 0.001, p = 0.002, respectively). Total-MMP2 and total-MMP9 activities are lower in control than benign (p < 0.001, p = 0.002, respectively) and cancer (p < 0.001, respectively). Total-MMP2 and MMP9 activities are also higher in cancer than benign (p = 0.004, p < 0.001) and HR (p = 0.008, p = 0.007, respectively). These results were not affected by age or inclusion/exclusion of donors with noninvasive cancer or atypical hyperplasia. Linear discriminant analysis revealed that HR donors are characterized by lower total-MMP2 and higher aMMP2. Overall group classification accuracy was 64.5%. Independent validation based on the leave-one-out cross validation approach gave an overall classification of 63%. Our study provides evidence supporting the potential role of serum MMP2/9 as biomarkers for breast disease classification.

Polymorphisms of the promoter regions of matrix metalloproteinases genes MMP-1 and MMP-9 in breast cancer

Matrix metalloproteinases play a crucial role in the cancer invasion and metastasis, angiogenesis and tumorigenicity. A single guanine insertion--the 1G/2G polymorphism in the promoter of the matrix metalloproteinase 1 (MMP-1) gene creates a binding site for the transcription factor AP-1 and thus may affect the transcription level of MMP-1. The C-->T substitution at the polymorphic site of the MMP-9 gene promoter results in a higher transcription activity of the T-allelic promoter trough the loss of binding site for a repressor protein. The aim of this work was to investigate the influence of 1G/2G and C-->T polymorphisms on the MMP-1 and MMP-9 level and therefore on the occurrence and progression of breast cancer. We investigated the distribution of genotypes and frequency of alleles of the 1G/2G and C-->T polymorphisms for 270 patients with breast cancer and 300 healthy women served as control. The genotypes were determined by RFLP-PCR. Additionally, we estimated the level of MMP-1 and MMP-9 antigens in tumor samples and normal breast tissue using ELISA. The levels of MMP-1 in tumor samples of node positive patients ware significantly higher than in samples of node negative patients (p<0.05). Increased level of MMP-9 correlates with Bloom-Richardson grading III (p<0.05), increased tumor size (p<0.05) and absence of estrogen and progesterone receptors (p<0.01). Additionally, both MMP-1 and MMP-9 levels were higher in tumor than in the normal breast tissue. We showed the higher risk of metastasis development in lymph node for the 2G/2G genotype (OR=2.14; CI 95% 1.24;3.69) and the 2G allele carriers (OR=1.68; CI 95% 1.19;2.39). We found correlation between the T allele (OR=2.61; CI 95% 1.33;4.87), 2G (OR=2.58; CI 95% 1.35;4.91) and malignance. The results suggest that MMP-1 is responsible for the local invasion and MMP-9 is associated with the malignance and the growth of the tumor. We suggest that the 2G allele of the 1G/2G MMP-1 gene polymorphism may be associated with the lymph node metastasis in patients with breast cancer and therefore it can be considered as a progression marker in this disease.

Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Breast Cancer with a Special Reference to Activator Protein-2, HER2, and Prognosis

In the present study, we investigated the expression and prognostic value of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer as well as their relation to transcription factor activator protein (AP)-2 and HER2 oncogene. The role of invasion and metastasis-promoting MMPs and their potential regulators, AP-2 and HER2, is currently still unclear in breast cancer. MMP-2 and MMP-9 expressions were analyzed immunohistochemically in a large prospective series of 421 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hospital (Kuopio, Finland). The relation of MMP-2 and MMP-9 expressions to AP-2, HER2, clinicopathological data, and survival was investigated. Both MMP-2 and MMP-9 were expressed in the cytoplasm of malignant and stromal cells. High expression of MMPs in carcinoma cells was related to small tumors (T1, stage I), whereas positive stromal expression of MMPs was associated with aggressive factors. High expression of MMP-2 and MMP-9 in carcinoma cells, but not in stromal cells, was related to high AP-2 expression. Positive stromal MMP-2 expression was associated with HER2 overexpression in the whole patient group and in the node-negative patient subgroup. Positive stromal MMP-9 expression was related to HER2 overexpression in estrogen receptor (ER)-positive disease. In the univariate survival analysis, positive stromal MMP-9 predicted shorter recurrence-free survival (RFS; P=0.0389) and breast cancer-related survival (BCRS; P=0.0081) in ER+ disease, especially in the subgroup of ER+ tumors of < or =2 cm in diameter (T1; P=0.0031 for RFS, and P=0.0089 for BCRS). High MMP-9 expression in cancer cells predicted longer RFS (P=0.0351) in the whole patient group. In the multivariate analysis of the whole patient group, the independent predictors of shorter RFS were reduced MMP-9 expression in carcinoma cells (P=0.0248), HER2 overexpression (P=0.0001), and advanced-stage disease (P=0.0002). Shorter BCRS was predicted by advanced-stage disease (P <0.0001). Expression of MMP-2 and MMP-9 in breast cancer seems to be partly related to expression of AP-2 and HER2. Positive stromal MMP-9 expression predicts poor survival in the hormone-responsive small tumors, whereas MMP-9 expression in carcinoma cells favors survival. Evaluation of MMP-9 expression seems to add valuable information on breast cancer prognosis.