Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rationale for matrix metalloproteinase (MMP) inhibition as a means to treat disease progression in breast cancer stems from the apparent involvement of MMPs in the hydrolysis of basement membranes during tumour cell invasion and subsequent metastasis. MMP-mediated matrix remodelling also appears to promote the growth of tumour cells, possibly by facilitating the proliferation and migration of endothelial cells and the neovascularization of tumour tissue. We found that transfection of the C127 breast cancer cell line by MMP-2 (gelatinase A), but not by MMP-1 or MMP-3 (collagenase and stromelysin respectively), gave rise to an invasive and metastatic phenotype. We were surprised to find that this phenotype depended not only on the catalytic properties of MMP-2 but also on properties associated with the MMP-2 non-catalytic C-terminal domain. Experiments with a synthetic gelatinase inhibitor revealed that a single dose could prevent the lungs of nude mice being colonized by the MMP-2 transfectants, and that the inhibitor had to be administered during or shortly after injection of the cells, indicating that an early event, such as the extravasation of the cells into the lung, is gelatinase-dependent in this system. In other studies employing long-term treatment with CT1746, an orally active gelatinase inhibitor, we have previously demonstrated a reduction in primary tumour growth rates, localized spread, and spontaneous metastasis, even when the treatment was commenced several days after tumour implantation. Furthermore, additive effects were recorded when gelatinase inhibitor therapy was combined with cytotoxic drug treatment. Since the gelatinase inhibitors can also inhibit bone resorption in vitro, these observations point to their potential for delaying disease recurrence and reducing rates of bone loss following conventional therapeutic strategies, in metastatic breast cancer.
 ...
PMID:Matrix metalloproteinases and metastatic cancer. 951 31

Matrix metalloproteinases (MMPs) play an important role in tumor cell invasion and metastasis. These processes require the dissolution of the basement membrane and invasion of the stromal matrix (ECM), and are mediated by MMPs. Consequently, MMP inhibitors may be attractive as new anticancer agents. To examine the potential contribution of collagenase-1 (MMP-1) in invasion of stromal matrix, we used the highly invasive and metastatic breast cancer cell line MDA-MB-231 as a model system. These cells express procollagenase-1 constitutively and this expression can be repressed by all-trans retinoic acid. Invasion of these cells into a collagen type I matrix was assessed by scanning electron microscopy (SEM), and was quantitated with a computer program and confocal laser scanning microscopy (CLSM). We found that MDA-MB-231 cells freely invaded the collagen type I matrix, suggesting that these cells possess a mechanism for activating the latent collagenase-1. In contrast, down-regulation of collagenase-1 expression by all-trans retinoic acid caused these cells to become less invasive. To confirm a role for collagenase-1 in mediating collagen type I invasion, assays were carried out in the presence of FN-439, an inhibitor of collagenase-1 enzyme activity. We found that in the presence of the proteinase inhibitor, invasion of type I collagen by MDA-MB-231 cells was also reduced. These results indicate that collagenase-1 produced by the breast tumor cells may enhance stromal matrix degradation by enabling the tumor cells to modulate their own invasive behavior, and suggest that decreasing collagenase-1 levels may be effective in breast cancer therapy.
 ...
PMID:Human breast cancer cells activate procollagenase-1 and invade type I collagen: invasion is inhibited by all-trans retinoic acid. 1043 8

Bone is the most preferred site for metastatic dissemination in breast cancer. The purpose of this study was to examine the expression of a set of antibodies that could serve as predictive biomarkers associated with breast cancer metastasis in a subset of sixteen (16) breast cancer patients who developed bone metastasis. The clinical and pathologic data were obtained, and tissue microarrays were constructed. Tissue microarray slides were stained for TFF-1, CXRC4, MMP1, PTHrP, HER2, CD44, FGFR3 and IL-11. The expression rates were compared between the metastatic breast cancer to bone (MBC-B) group and a group of sixty-four (64) primary breast cancer (PBC). The results demonstrated that MBC-B group patients were more likely to be HER2 positive (P = 0.016). There was no significant difference on estrogen receptor or progesterone receptor expression between MBC-B group and PBC group (P > 0.05). There was a high expression of CXCR4, MMP-1, CD44, TFF-1, PTHrP, FGFR3 and IL-11, in both, PBC and MBC-B, and no significant differences between the groups were identified. We found that tumors associated with bone metastasis tended to be larger than 2 cm. The high morbidity associated to metastatic breast cancer prompts the identification of predictive biomarkers of relapse of breast tumors to categorize patients at high risk of bone metastasis and serve as targeted therapy.
 ...
PMID:Biomarker profile in breast carcinomas presenting with bone metastasis. 2012 81

More than 90% of cancer patient mortality is attributed to metastasis. In this study, we investigated a role for the lysyl oxidase-related enzyme lysyl oxidase-like 2 (LOXL2) in breast cancer metastasis, in both patient samples and in vivo models. Analysis of a published microarray data set revealed that LOXL2 expression is correlated with metastasis and decreased survival in patients with aggressive breast cancer. In immunocompetent or immunocompromised orthotopic and transgenic breast cancer models we showed that genetic, chemical or antibody-mediated inhibition of LOXL2 resulted in decreased metastasis. Mechanistic investigations revealed that LOXL2 promotes invasion by regulating the expression and activity of the extracellular proteins tissue inhibitor of metalloproteinase-1 (TIMP1) and matrix metalloproteinase-9 (MMP9). We found that LOXL2, TIMP1, and MMP9 are coexpressed during mammary gland involution, suggesting they function together in glandular remodeling after weaning. Finally, we found that LOXL2 is highly expressed in the basal/myoepithelial mammary cell lineage, like many other genes that are upregulated in basal-like breast cancers. Our findings highlight the importance of LOXL2 in breast cancer progression and support the development of anti-LOXL2 therapeutics for the treatment of metastatic breast cancer.
 ...
PMID:LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. 3157 31

Molecular and biochemical expressions of matrix metalloproteinases in breast cancer tissue and cells offers promise in helping us understand the breast cancer microenvironment, and also in the future it is hoped this will improve its detection, treatment and prognosis. In a retrospective study recently published in BMC Cancer, microenvironment predisposing to breast cancer progression, metastatic behavior and the expression of matrix metalloproteinase-1 (MMP-1) and its correlation with well-known biochemical, molecular and clinicopathologic factors in breast cancer cells and cancer-associated stromal cells was examined; this study also analyzed patient survival in different breast cancer subtypes. The positive correlation in breast tumor and stromal cells between MMP-1 expression and several markers of tumor grade and stage provide us with some useful new insights into important questions about the molecular profiling of the stromal microenvironment in metastatic breast cancer. The study showed that MMP-1 expression is strongly associated with poor clinical outcome, so now we look forward to future larger studies in breast cancer patients in which we can relate wider MMP molecular profiling to identify lethal tumor and stromal microenvironments predisposing to breast cancer progression, metastatic behavior and poor prognosis. Please see related article http://www.biomedcentral.com/1471-2407/11/348.
 ...
PMID:What does matrix metalloproteinase-1 expression in patients with breast cancer really tell us? 2183 86

Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and l-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation.
 ...
PMID:Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis. 2604 46

Milwaukee Shoulder Syndrome (MSS) is a painful progressive arthropathy in which hydroxyapatite crystal deposition in synovial tissue induces lysosomal release of collagenase and neutral proteases. These enzymes are destructive to periarticular tissue, including the synovium, articular cartilage, rotator cuff muscles, and the intrasynovial cortical bone. MSS predominantly occurring in women (90%) over the age of 70 years of age with a clinical history marked by recurrent joint effusions and pain, which classically worsens at night. Our patient is a 69-year-old woman who presented with progressive shoulder pain, most prominent at night, with limited range of motion and swelling; intermittent discharge; and intermittent neck pain that radiated to her right upper extremity. Her medical history was notable for invasive carcinoma of the right breast treated with mastectomy and radiation. She was also treated with radiation therapy for right shoulder pain and a lucent right shoulder lesion presumed to be metastatic breast cancer. The remainder of her medical history consists of hypertension, diabetes mellitus, hyperlipidemia, and uneventful bilateral total knee arthroplasties. At presentation, she denied constitutional symptoms. Based on the patient's history and physical exam the differential diagnosis included primary and metastatic malignancy, radiation induced sarcoma and necrosis, infection, Charcot disease, and crystal arthropathies. Physical exam, laboratory findings, and imaging studies led us to the diagnosis of MSS.
 ...
PMID:Shoulder Lesion in a 69 Year Old Woman. 2977 93