Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies demonstrate that cyclooxygenase-2 (COX-2) expression is frequently associated with lymph node metastasis. However, the mechanism by which COX-2 increases the invasion of cancer cells to lymph node is unclear. CCR7 is a chemokine receptor that plays important roles in the mediation of migration of leukocytes and dendritic cells toward lymphatic endothelial cells (LECs) that express receptor ligand CCL21. We found that treatment of prostaglandin E(2) or ectopic expression of COX-2 in MCF-7 cells up-regulated CCR7 expression. On the contrary, knockdown of COX-2 by small hairpin RNA reduced CCR7 in COX-2-overexpressing MDA-MB-231 cells. Interaction of CCR7 and CCL21 was important for the migration of breast cancer cells toward LECs because antibodies against these two molecules inhibited the migration. We also found that COX-2 increased CCR7 expression via the EP2 and EP4 receptor in breast cancer cells. EP2 and EP4 agonists stimulated CCR7 in MCF-7 cells, whereas antagonists or small hairpin RNA of EP2 and EP4 attenuated CCR7 in MDA-MB-231 cells. Protein kinase A and AKT kinase were involved in COX-2-induced CCR7. Pathological analysis demonstrated that COX-2 overexpression was associated with CCR7, EP2, and EP4 expressions in breast tumor tissues. In addition, CCR7 expression in COX-2-overexpressing tumors was significantly correlated with lymph node metastasis. Collectively, we suggest that CCR7 is a down-stream target for COX-2 to enhance the migration of breast cancer cells toward LECs and to promote lymphatic invasion.
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PMID:Cyclooxygenase-2 up-regulates CCR7 via EP2/EP4 receptor signaling pathways to enhance lymphatic invasion of breast cancer cells. 1831 53

Cruciferous vegetables are thought to protect against numerous types of cancer. 3,3'-Diindolylmethane (DIM) is an acid-catalyzed product generated during the consumption of cruciferous vegetables and appears to be chemoprotective for breast cancer. The interaction between the chemokine receptor, CXCR4, and its unique ligand, CXCL12, is known to mediate the progression and metastasis of breast and other cancers. Organs to which these cancers metastasize secrete CXCL12, which binds to CXCR4 expressed on the surface of primary cancer cells. This process subsequently stimulates the invasive properties of the cancer cells and attracts them to the preferred organ sites of metastases. We have found that DIM down-regulates both CXCR4 and CXCL12 in MCF-7 and MDA-MB-231 breast cancer cells as well as in BG-1 ovarian cancer cells at the transcriptional level and in an estrogen-independent manner. We demonstrate that the potential of MDA-MB-231 and BG-1 cells for chemotaxis and invasion towards CXCL12, but not towards IL-6 or fetal bovine serum, respectively, is inhibited by DIM. Furthermore, we show that DIM down-regulates CXCR4 under hypoxia and CXCL12 under estradiol-inducing conditions. Our data suggest that one mechanism whereby DIM protects against breast, ovarian, and possibly other cancers is through the repression of CXCR4 and/or CXCL12, thereby lowering the invasive and metastatic potential of these cells.
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PMID:CXCR4 and CXCL12 down-regulation: a novel mechanism for the chemoprotection of 3,3'-diindolylmethane for breast and ovarian cancers. 1837 71

Vaccination of patients with dendritic cell (DC)/breast carcinoma fusions stimulated antitumor immune responses in a majority of patients with metastatic disease but only a subset demonstrate evidence of tumor regression. To define the factors that limit vaccine efficacy, we examined the biological characteristics of DC/breast carcinoma fusions as APCs and the nature of the vaccine-mediated T cell response. We demonstrate that fusion of DCs with breast carcinoma cells up-regulates expression of costimulatory and maturation markers and results in high levels of expression of IL-12 consistent with their role as activated APCs. Fusion cells also express the chemokine receptor CCR7, consistent with their ability to migrate to the draining lymph node. However, DC/breast cancer fusions stimulate a mixed T cell response characterized by the expansion of both activated and regulatory T cell populations, the latter of which is characterized by expression of CTLA-4, FOXP3, IL-10, and the suppression of T cell responses. Our results demonstrate that IL-12, IL-18, and TLR 9 agonist CpG oligodeoxynucleotides reduce the level of fusion-mediated regulatory T cell expansion. Our results also demonstrate that sequential stimulation with DC/breast carcinoma fusions and anti-CD3/CD28 results in the marked expansion of activated tumor-specific T cells. These findings suggest that DC/breast carcinoma fusions are effective APCs, but stimulate inhibitory T cells that limit vaccine efficacy. In contrast, exposure to TLR agonists, stimulatory cytokines, and anti-CD3/CD28 enhances vaccine efficacy by limiting the regulatory T cell response and promoting expansion of activated effector cells.
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PMID:Fusions of dendritic cells with breast carcinoma stimulate the expansion of regulatory T cells while concomitant exposure to IL-12, CpG oligodeoxynucleotides, and anti-CD3/CD28 promotes the expansion of activated tumor reactive cells. 1856 47

The CXCR4 chemokine receptor is a seven transmembrane G protein-coupled receptor present on the surface of various cells including cancer cells. The CXCR4 receptor contributes to the induction of several intracellular signalling pathways that enhance survival, proliferation, and migration of malignant cells. We observed that tamoxifen (Tam) reduced the CXCR4 transcript and protein levels in MCF-7 breast cancer cells. However, we did not see a Tam effect on CXCR4 transcript and protein levels in MCF-7(LVMT3B) cells with RNA interference-mediated knockdown of DNMT3B. We also observed that Tam significantly increased, for several hours, the expression of enzymatically active DNMT3B splice variants in MCF-7 cells. However, there was no Tam effect on these DNMT3B splice variants' expression in MCF-7(LVMT3B) cells. Bisulfite sequencing suggests that Tam may reduce CXCR4 expression via increased methylation of cytosine in the cytosine-guanosine (CpG) dinucleotide island of the CXCR4 promoter of MCF-7 breast cancer cells. Our findings suggest that Tam induces an increase in DNMT3B expression that is associated with the increase of CpG dinucleotide methylation in the CXCR4 promoter and significant reduction of CXCR4 gene expression in MCF-7 cells.
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PMID:Down-regulation of CXCR4 expression by tamoxifen is associated with DNA methyltransferase 3B up-regulation in MCF-7 breast cancer cells. 1901 22

Withanolides are C(28) steroidal lactones isolated from plants that exhibit potent anti-cancer activity. The chemokine receptor CCR7 is important for lymphatic invasion of cancer cells and is overexpressed in metastatic breast cancer cells. A bioactive withanolide tubocapsanolide A (Tubo A) suppressed NF-kappaB-mediated CCR7 expression in breast cancer cells and attenuated their migration toward lymphatic endothelial cells. Chromatin immunoprecipitation assay confirmed that binding of NF-kappaBto the consensus site localized at the -398/-389 of human CCR7 promoter was repressed by Tubo A. Tubo A inhibited IkappaB kinase (IKK) and p38 kinase and downstream mitogen and stress-activated protein kinase 1 (MSK1) activity to reduce IkappaB degradation and to suppress NF-kappaB activation. Co-expression of IKK and MSK1 fully rescued Tubo A-induced inhibition. In addition, ectopic expression of transforming growth factor-beta-activating kinase (TAK1), the common upstream kinase of IKK and MSK1, also completely reversed the inhibition by Tubo A. Most importantly, Tubo A reduced NF-kappaB activation, CCR7 expression, and lymph node metastasis of breast cancer in vivo. We conclude that Tubo A inhibits TAK1 to repress NF-kappaB-induced CCR7 expression in breast cancer cells and suggest that Tubo A may be useful for the prevention of lymphatic invasion of breast cancer cells.
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PMID:Tubocapsanolide A inhibits transforming growth factor-beta-activating kinase 1 to suppress NF-kappaB-induced CCR7. 1904 61

Chemokines comprise a superfamily of at least 46 cytokines that were initially described based on their ability to bind to 18 to 22 G protein-coupled receptors to induce the directed migration of leukocytes to sites of inflammation or injury. In addition to mediating cellular migration, chemokine/chemokine receptor pairs have been shown to affect many cellular functions, including survival, adhesion, invasion, and proliferation, and to regulate circulating chemokine levels. Most malignancies also express one or more chemokine receptors. Early studies established a role for CXCR4 and CXCR7 in mediating breast cancer metastasis, but other chemokine receptors, including CXCR3, now are implicated in several malignancies as biomarkers of tumor behavior as well as potential therapeutic targets. This review summarizes our current understanding regarding the contribution of CXCR4 and CXCR3 to tumor behavior and how receptor expression is regulated, transduces intracellular signals, and contributes at the molecular level to tumor behavior. It also describes recent therapeutic approaches that target these receptors or their ligands.
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PMID:The chemokine receptors CXCR4 and CXCR3 in cancer. 1921 44

The chemokine and chemokine receptor families have important roles in tumorigenesis. Although CXCR4 and CCR7 have been reported to be associated with cancer metastasis, the role of other chemokine receptors in cancer is poorly understood. We explored the status of CXCR6 in hypoxia-induced cell migration. Breast cancer cells and human umbilical vein endothelial cells (HUVEC) expressed CXCR6, and showed appreciable chemotactic migration to CXCL16. Significant accumulation of CXCR6 mRNA and protein during hypoxia was observed. Overexpression of CXCR6 increased cell migration, and knockdown of CXCR6 attenuated hypoxia-mediated cell migration and MMP-2 secretion. To investigate possible mechanisms regulating CXCR6 expression during hypoxia, we detected the expression of HIFs and found that HIF-1alpha was involved in CXCR6 regulation. CXCR6 and HIF-1alpha were highly expressed in breast cancer lymph nodes metastases. Our data suggest CXCR6 contributes significantly to cell migration during hypoxia.
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PMID:Chemokine C-X-C motif receptor 6 contributes to cell migration during hypoxia. 1923 Oct 68

The interaction between chemokines and their G-protein-coupled receptors plays an important role in promoting metastasis of different kinds of human cancers. However, the expression of an atypical chemokine receptor, CCX-CKR, which serves as a decoy receptor to attract chemokines, inhibits the growth and metastasis of breast cancer by sequestration of chemokines.
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PMID:Regulation of breast cancer metastasis by atypical chemokine receptors. 1938 22

The proliferative capacity of cancer cells is regulated by factors intrinsic to cancer cells and by secreted factors in the microenvironment. Here, we investigated the proto-oncogenic potential of the chemokine receptor, CCR5, in MCF-7 breast cancer cell lines. At physiological levels, CCL5, a ligand for CCR5, enhanced MCF-7.CCR5 proliferation. Treatment with the mTOR inhibitor, rapamycin, inhibited this CCL5-inducible proliferation. Because mTOR directly modulates mRNA translation, we investigated whether CCL5 activation of CCR5 leads to increased translation. CCL5 induced the formation of the eIF4F translation initiation complex through an mTOR-dependent process. Indeed, CCL5 initiated mRNA translation, shown by an increase in high-molecular-weight polysomes. Specifically, we show that CCL5 mediated a rapid up-regulation of protein expression for cyclin D1, c-Myc and Dad-1, without affecting their mRNA levels. Taken together, we describe a mechanism by which CCL5 influences translation of rapamycin-sensitive mRNAs, thereby providing CCR5-positive breast cancer cells with a proliferative advantage.
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PMID:CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation. 1960 6

The chemokine receptor, CXCR4, and its specific ligand, CXCL12, have been proven to regulate the directional trafficking and invasion of breast cancer cells to sites of metastases, and similar phenomena have also been identified in many malignant tumors that aberrantly overexpress CXCR4. Therefore, blocking the interaction between CXCR4 and CXCL12 is considered a possible approach to efficiently prevent cancer metastasis. Employing a cellular phenotypic knockout strategy based on intrakines, we developed a novel recombinant chimeric protein, TAT/54R/KDEL, which contains three distinct functional domains: CXCL12/54R, a mutant of CXCL12 with CXCR4 antagonism, as well as HIV-derived TAT (47-57) and an endoplasmic reticulum retention four-peptide sequence KDEL that links at its NH(2) and COOH termini, respectively. Using the MOLT-4 cell line, which expressed CXCR4 highly and stably in vitro, we determined that TAT/54R/KDEL was able to efficiently transfer into the endoplasmic reticulum of tumor cells, where it specifically binds to the newly synthesized CXCR4 and prevents the latter from reaching the surface. Chemotaxis assays showed that the cells treated with TAT/54R/KDEL failed to migrate toward CXCL12. Furthermore, we observed that the systemic treatment of TAT/54R/KDEL could impair lung metastasis in a highly metastatic mammary cancer cell line, 4T1 cells, with the decrease of CXCR4 on their membrane. Our results suggest that the phenotypic knockout strategy of CXCR4 using a novel recombinant protein TAT/54R/KDEL might be a possible approach for inhibiting relative tumor metastasis mediated by CXCR4/CXCL12 interaction.
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PMID:Phenotypic knockout of CXCR4 by a novel recombinant protein TAT/54R/KDEL inhibits tumors metastasis. 1982 96


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