Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 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.
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PMID:Matrix metalloproteinases and metastatic cancer. 951 31

Recent trials comparing single-agent vs combination therapy in metastatic breast cancer suggest that it may be time to reconsider the belief that combination chemotherapy is the gold standard of treatment. Based on the limited randomized trial data available to date, high-dose chemotherapy with stem-cell rescue should not be viewed as "state-of-the art" treatment for metastatic disease and should be used only in the context of clinical trials. Recent trials have explored the optimal dosing and scheduling of the taxanes, as well as the possible role of these agents in combination regimens. Capecitabine (Xeloda), a new oral fluoropyrimidine, appears to be comparable in efficacy to CMF (cyclophosphamide, methotrexate, and fluorouracil), and preclinical data suggest possible synergy between this agent and the taxanes. Other promising agents under study include liposome-encapsulated doxorubicin (TLCD-99), an immunoconjugate linking a chimeric human/mouse monoclonal antibody to doxorubicin molecules; MTA (LY231514), a multitargeted antifolate; and marimistat, a broad-spectrum matrix metalloproteinase inhibitor. Tamoxifen (Nolvadex) remains the most important hormonal agent, but new antiestrogens and selective estrogen receptor modulators (SERMs) may provide alternatives. The potential role of new aromatase inhibitors as first-line hormonal agents requires further study. Finally, the possible synergy between trastuzumab (Herceptin), a recombinant humanized monoclonal antibody to the HER-2/neu protein, and paclitaxel (Taxol) is being studied in two clinical trials.
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PMID:Update on the management of advanced breast cancer. 1035 85

Expression of adhesion receptor integrin alphavbeta3 in an activated functional form strongly promotes metastasis in human breast cancer cells. Here, we report that alphavbeta3 cooperates with matrix metalloproteinase type 9 (MMP-9) in breast cancer cell migration. This cooperation is regulated by the activation state of the integrin. Expression of activated alphavbeta3 in metastatic variants of MDA-MB 435 human breast cancer cells and primary metastatic cells from breast cancer patients strongly enhanced migration toward vitronectin and fibrinogen. This enhancement was mediated by a soluble factor produced by breast cancer cells expressing activated alphavbeta3. When transferred, this factor also up-regulated alphavbeta3-dependent migration of breast cancer cells that express the nonactivated integrin. The factor was identified as metalloproteinase MMP-9. Whereas all tested breast cancer cell variants produced latent MMP-9, only those with activated alphavbeta3 produced the mature form of this metalloproteinase. Recombinant mature MMP-9, but not latent MMP-9 or either form of MMP-2, enhanced alphavbeta3-dependent breast cancer cell migration. The migratory response was inhibited by tissue inhibitors of metalloproteinase or when MMP-9 was depleted from the inducing supernatants. The results indicate a causal relationship between the expression of activated integrin alphavbeta3 and production of enzymatically active MMP-9 in metastatic breast cancer cells. These molecules cooperate to enhance breast cancer cell migration toward specific matrix proteins, and this may contribute to the strongly enhanced metastatic capacity of breast cancer cells that express activated alphavbeta3.
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PMID:Activated integrin alphavbeta3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells. 1287 88

Mammary epithelial cells constitutively expressing Id-1 protein are unable to differentiate, acquire the ability to proliferate, and invade the extracellular matrix. In addition, Id-1 is aberrantly over-expressed in aggressive and metastatic breast cancer cells, as well as in human breast tumor biopsies from infiltrating carcinomas, suggesting Id-1 might be an important regulator of breast cancer progression. We show that human metastatic breast cancer cells become significantly less invasive in vitro and less metastatic in vivo when Id-1 is down-regulated by stable transduction with antisense Id-1. Expression of the matrix metalloproteinase MT1-MMP is decreased in proportion to the decrease in Id-1 protein levels, representing a potential mechanism for the reduction of invasiveness. Further, to more accurately recapitulate the biology of and potential therapeutic approaches to tumor metastasis, we targeted Id-1 expression systemically in tumor-bearing mice by using a nonviral approach. We demonstrate significant reduction of both Id-1 and MT1-MMP expressions as well as the metastatic spread of 4T1 breast cancer cells in syngeneic BALB/c mice. In conclusion, our studies have identified Id-1 as a critical regulator of breast cancer progression and suggest the feasibility of developing novel therapeutic approaches to target Id-1 expression to reduce breast cancer metastasis in humans.
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PMID:Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis. 1457 51

Tissue inhibitor of metalloproteinases (TIMP)-2 is a highly conserved molecule, which binds both active and latent matrix metalloproteinase (MMP)-2. TIMP-2 is also involved in the activation of MMP-2 on the cell surface. A quantitative enzyme-linked immunosorbent assay (ELISA) was established and optimized for measurement of TIMP-2 in plasma. The capturing antibody in the ELISA was a monoclonal, while the detecting antibody was a chicken polyclonal antibody recognizing the native form of human TIMP-2. The levels of TIMP-2 were measured in ethylenediaminetetraacetic acid (EDTA) and citrate plasma from healthy donors. The median values were determined as 163 ng/ml (n = 186) with a range of 109-253 ng/ml for EDTA plasma and 139 ng/ml (n = 77) with a range of 95-223 ng/ml for citrate plasma. The TIMP-2 concentration in citrate plasma from 15 patients with advanced, stage IV breast cancer had a median value of 160 ng/ml, only slightly higher but statistically distinguishable from the level found in citrate plasma from the healthy donors. In addition, the TIMP-2 concentration in EDTA plasma from colorectal cancer patients revealed a significantly higher level in plasma from patients with Dukes stage A (P = 0.01) compared with patients with more advanced Dukes stages.
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PMID:Quantification of tissue inhibitor of metalloproteinases 2 in plasma from healthy donors and cancer patients. 1588 37

Currently, there is no effective therapy for metastatic breast cancer after surgery, radiation, and chemotherapy have been used against the primary tumor. Because curcumin suppresses nuclear factor-kappaB (NF-kappaB) activation and most chemotherapeutic agents activate NF-kappaB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis. We tested this hypothesis using paclitaxel (Taxol)-resistant breast cancer cells and a human breast cancer xenograft model. As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-kappaB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IkappaBalpha kinase activation and IkappaBalpha phosphorylation and degradation. Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-kappaB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-kappaB and NF-kappaB-regulated gene products.
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PMID:Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. 1624 23

Metastatic cancer cells increase glucose consumption and metabolism via glycolysis, producing large quantities of lactate. Recent work has shown that lactate efflux is mediated by monocarboxylate transporters (MCT), which are composed of a catalytic unit (MCT) and an accessory subunit (CD147), comprising the functional lactate transporter. CD147, an extracellular matrix metalloproteinase (MMP) inducer, is highly expressed in metastatic cancer cells. Because aerobic glycolysis is a hallmark of metastatic cancer, we examined whether increases in CD147 expression were linked to MCT expression in MDA-MB-231, a highly metastatic breast cancer cell line. MCT4 mRNA and protein expression were increased in MDA-MB-231 cells compared with cells derived from normal mammary tissue. MCT4 colocalized with CD147 in the plasma membrane and in membrane blebs shed from the cell surface. Small interfering RNA-mediated silencing of MCT4 impaired the maturation and trafficking of CD147 to the cell surface, resulting in accumulation of CD147 in the endoplasmic reticulum. Silencing MCT4 also resulted in fewer membrane blebs and decreased migration of MDA-MB-231 cells in vitro. Knockdown of CD147 resulted in loss of MCT4 in the plasma membrane and accumulation of the transporter in endolysosomes. These studies establish for the first time that increased expression of CD147 in metastatic cancer cells is coupled to the up-regulation of MCT4. The synergistic activities of the MCT/CD147 complex could facilitate migration of tumor cells by CD147-mediated MMP induction and lactate-stimulated angiogenesis and hyaluronan production. These data provide a molecular link between two hallmarks of metastatic cancer: the glycolytic switch and increased expression of CD147.
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PMID:Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. 1748 29

The skeleton is a preferred site of metastasis in patients with disseminated breast cancer. We have used 4T1 mouse mammary carcinoma cells, which metastasize to bone from the mammary fat pads of immunocompetent mice, to identify novel genes involved in this process. In vivo selection of parental cells resulted in the isolation of independent, aggressively bone metastatic breast cancer populations with reduced metastasis to the lung. Gene expression profiling identified osteoactivin as a candidate that is highly and selectively expressed in aggressively bone metastatic breast cancer cells. These cells displayed enhanced migratory and invasive characteristics in vitro, the latter requiring sustained osteoactivin expression. Osteoactivin depletion in these cells, by small interfering RNA, also lead to a loss of matrix metalloproteinase-3 expression, whereas forced osteoactivin expression in parental 4T1 cells was sufficient to elevate matrix metalloproteinase-3 levels, suggesting that this matrix metalloproteinase may be an important mediator of osteoactivin function. Overexpression of osteoactivin in an independent, weakly bone metastatic breast cancer cell model significantly enhanced the formation of osteolytic bone metastases in vivo. Finally, high levels of osteoactivin expression in primary human breast cancers correlate with estrogen receptor-negative status and increasing tumor grade. Thus, we have identified osteoactivin as a protein that is expressed in aggressive human breast cancers and is capable of promoting breast cancer metastasis to bone.
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PMID:Osteoactivin promotes breast cancer metastasis to bone. 1795 1

We are interested in two aspects of a given type of metastatic breast cancer: which potentially cancer-relevant genes are expressed and which factors determine invasiveness. Using reverse transcription real-time PCR, we detected gene expression of 26 matrix metalloproteinases (MMPs) in MDA-MB-231 breast cancer cells, including those of MMP-12, MMP-16 variant 2, MMP-19, MMP-20, MMP-21, MMP-23, MMP-24, MMP-25, MMP-25 variant 2, MMP-L1, MMP-26, MMP-27, and MMP-28, in contrast to the 13 MMPs detected until now in these cells. We found that MMP genes are expressed at widely different levels in these cells, over five orders of magnitude. After individual siRNA-induced depletions, we found that six additional species of cancer cell MMPs promote invasiveness in MDA-MB-231 cells: MMP-3, MMP-11, MMP-12, MMP-17, MMP-19, and MMP-23, thus raising the total to 12 endogenous MMPs which do so in these cells. The data support the conclusion that some cancer cell MMPs, although expressed at low levels, are needed for cancer trait in MDA-MB-231 cells, and that several endogenous MMPs play non-redundant roles in this process. The mRNA level of MMP-11, but not of other MMPs, rose substantially following individual siRNA-targeted depletion of cancer cell MMP-17 mRNA, while no MMP mRNA increased appreciably after degradation of other MMP mRNAs. This supports the conclusion that MMP-17 may be a member of an intracellular signaling pathway which downregulates MMP-11 mRNA.
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PMID:Additional MDA-MB-231 breast cancer cell matrix metalloproteinases promote invasiveness. 1828 80

Metastasis is a multistep process that involves the deregulation of oncogenes and tumor suppressors beyond changes required for primary tumor formation. RHOB is known to have tumor suppressor activity, and its knockdown is associated with more aggressive tumors as well as changes in cell shape, migration, and adhesion. This study shows that oncogenic microRNA, miR-21, represses RHOB expression by directly targeting the 3' untranslated region. Loss of miR-21 is associated with an elevation of RHOB in hepatocellular carcinoma cell lines Huh-7 and HepG2 and in the metastatic breast cancer cell line MDA-MB-231. Using in vitro models of distinct stages of metastasis, we showed that loss of miR-21 also causes a reduction in migration, invasion, and cell elongation. The reduction in migration and cell elongation can be mimicked by overexpression of RHOB. Furthermore, changes in miR-21 expression lead to alterations in matrix metalloproteinase-9 activity. Therefore, we conclude that miR-21 promotes multiple components of the metastatic phenotype in vitro by regulating several important tumor suppressors, including RHOB.
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PMID:Overexpression of miR-21 promotes an in vitro metastatic phenotype by targeting the tumor suppressor RHOB. 2046 Apr 3


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