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

Although it is causative for many types of cancers, experimental and epidemiological evidence suggest that 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) may in fact protect against breast cancer. The mechanism(s) for this protection remain unclear. In an attempt to further elucidate this mechanism, we performed a microarray experiment to identify genes that were modulated upon dioxin treatment. We found that dioxin downregulated the messenger RNAs for the G-protein-coupled receptor, CXCR4, as well as its unique chemokine ligand, CXCL12, in MCF-7 breast cancer cells. We demonstrated that the corresponding proteins are also downregulated by dioxin. The interaction between CXCR4 and CXCL12 plays a central role in the metastasis of breast cancer, as disruption of the CXCL12/CXCR4 axis has been shown to limit the metastasis of breast cancer cells to the lung in mice. Utilizing an in vitro chemotaxis assay, we demonstrate that dioxin specifically inhibits the migration of MCF-7 cells toward CXCL12. We also show that dioxin reduces CXCR4 under hypoxia and CXCL12 under estradiol-induced conditions in MCF-7 cells. Finally, as the CXCR4/CXCL12 axis is implicated in the progression of numerous types of cancer, we identified several other cancer cell lines in which dioxin modulates CXCR4 and CXCL12 levels. We therefore propose that one mechanism whereby dioxin may protect against breast cancer is via downregulation of CXCR4 and CXCL12, thereby inhibiting progression of the disease. Further, other nontoxic ligands for the aryl hydrocarbon receptor (selective AHR modulators) may exert their protective effects by a similar mechanism.
 ...
PMID:A proposed mechanism for the protective effect of dioxin against breast cancer. 1751 23

In previous studies, the chemokine CCL21 has shown biological activities that include T cell, natural killer (NK) cell, and dendritic cell (DC) chemoattraction. The goal of this study was to determine the effects of administering CCL21 to orthotopic mammary tumors in terms of impact on tumor growth rate, immune cell infiltration of the primary tumor and survival. We found that a single intratumoral administration of CCL21 slowed the growth of orthotopic mammary tumors and increased intratumoral infiltration by T cells, NK cells and DCs. CCL21 intratumoral administration also prolonged the survival of tumor-earing mice. Furthermore, mice that received intratumoral neoadjuvant CCL21 ior to surgical resection of tumors survived significantly longer than control mice. The urviving neoadjuvant CCL21-reated mice, when challenged again with cl-6, had significantly slower rate of tumor growth than challenged control mice. Thus, our ata indicate that CCL21 treatment prior to mammary tumor resection can significantly rolong survival and increase resistance to subsequent tumor challenge. Overall, our indings suggest that intratumoral administration of CCL21 has potential as a neoadjuvant mmunotherapy for breast cancer.
 ...
PMID:CCL21 is an effective surgical neoadjuvant for treatment of mammary tumors. 1761 42

Recent studies have highlighted the possible involvement of chemokines and their receptors in breast cancer progression and metastasis. Chemokines and their receptors constitute a superfamily of signalling factors whose prognosis value in breast cancer progression remains unclear. We will examine here the expression pattern of chemokines and their receptors in mammary gland physiology and carcinogenesis. The nature of the cells producing chemokines or harboring chemokine receptors appears to be crucial in certain conditions for example, the infiltration of the primary tumor by leukocytes and angiogenesis. In addition, chemokines, their receptors and the interaction with glycosaminoglycan (GAGs) are key players in the homing of cancer cells to distant metastasis sites. Several lines of evidence, including in vitro and in vivo models, suggest that the mechanism of action of chemokines in cancer development involves the modulation of proliferation, apoptosis, invasion, leukocyte recruitment or angiogenesis. Furthermore, we will discuss the regulation of chemokine network in tumor neovascularity by decoy receptors. The reasons accounting for the deregulation of chemokines and chemokine receptors expression in breast cancer are certainly crucial for the comprehension of chemokine role in breast cancer and are in several cases linked to estrogen receptor status. The targeting of chemokines and chemokine receptors by antibodies, small molecule antagonists, viral chemokine binding proteins and heparins appears as promising tracks to develop therapeutic strategies. Thus there is significant interest in developing strategies to antagonize the chemokine function, and an opportunity to interfere with metastasis, the leading cause of death in most patients.
 ...
PMID:Chemokines: novel targets for breast cancer metastasis. 1771 37

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.
 ...
PMID:Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. 1791 89

Lymph node metastasis is the main prognosis factor in a number of malignancies, including breast carcinomas. The means by which lymph node metastases arise is not fully understood, and many questions remain about their importance in the further spread of breast cancer. Nevertheless, a number of key cellular and molecular mechanisms of lymphatic metastasis have been identified. These include induction of intra- or peri-tumoral lymphangiogenesis or co-option of existing lymphatic vessels to allow tumour cells to enter the lymphatics, although it remains to be established whether this is primarily an active or passive process. Gene expression microarrays and functional studies in vitro and in vivo, together with detailed clinical observations have identified a number of molecules that can play a role in the genesis of lymph node metastases. These include the well-recognised lymphangiogenic cytokines VEGF-C and VEGF-D as well as chemokine-receptor interactions, integrins and downstream signalling pathways. This paper briefly reviews current clinical and experimental evidence for the underlying mechanisms and significance of lymphatic metastasis in breast cancer and highlights questions that still need to be addressed.
 ...
PMID:Lymphatic metastasis in breast cancer: importance and new insights into cellular and molecular mechanisms. 1798

Here we show the increase of invasion of three breast cancer cell lines (8701-BC, MDA-MB-231 and SKBR3) upon long-term co-incubation with culture medium of normal microvascular endothelial cells (MVEC) and normal breast epithelial cells (HB2). The enhancement of invasion relied on the interaction of microvascular endothelial cell and normal breast epithelial cell CXCL12 (SDF1) chemokine, whose expression by breast cancer cells was very low, with the cognate CXCR4 receptor of malignant cells, which resulted in over-expression of the urokinase-type plasminogen activator receptor (uPAR) on their surfaces. uPAR over-expression, showed by RT-PCR and Western blotting, was paralleled by increased urokinase-type plasminogen activator (uPA) partitioning on the cell surface with respect to the fluid phase, as demonstrated by zymography. Long-term interaction of SDF1 with CXCR4 stimulated sustained activation of JNK phosphorylation. Blocking antibodies to CXCR4 were able to block the endothelial/epithelial cell-dependent enhancement of invasion, as well as to inhibit SDF1-CXCR4-dependent JNK phosphorylation and uPAR over-expression of malignant cells. We suggest that acquisition of the angiogenic phenotype by breast cancer cells triggers an amplification loop, in which endothelial cells and normal breast epithelial cells of the tumour cooperate to provide facilitated routes to cell invasion and metastasis and to enhance the aggressive phenotype of cancer cells.
 ...
PMID:Endothelial cells and normal breast epithelial cells enhance invasion of breast carcinoma cells by CXCR-4-dependent up-regulation of urokinase-type plasminogen activator receptor (uPAR, CD87) expression. 1818 29

The chemokine Stromal-derived factor-1alpha (SDF-1alpha) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1alpha is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembrane (TM), GPR and are involved in tumor promotion. SDF-1alpha regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFkappaB) activation. This study focuses on the mechanism of activation at low SDF-1alpha in MCF12A non-tumorigenic breast cells. Reporter gene assays with the 5' flanking region of Tac1 (exon 1 omitted) and co-transfection with the repressor of cAMP response element (CREB) (ICER), and transfection with the CRE sites mutated, verified critical roles for CRE sites in SDF-1alpha-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1alpha phosphorylated CREB (P-CREB) via Galpha(i)2-PI3K-protein kinase C (PKC)zeta-p38-extracellular signal-regulated kinase (ERK) and no evidence of cAMP-PKA pathway. This observation is different from previous studies that reported CREB-phosphorylated PKA pathway in the activation of Tac1 in bone marrow stromal cells. This suggests cell specificity in Tac1 expression. In conclusion, this study reports on a non-canonical pathway in Tac1 activation by SDF-1alpha. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.
 ...
PMID:Stromal-derived factor-1alpha induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells. 1831 70

Metastasis contributes to more than 90% of mortality in breast cancer. Critical stages in the development of aggressive breast cancer include growth of the primary tumours, and their abilities to spread to distant organs, colonize and establish an independent blood supply. The integrin family of cell adhesion receptors is essential to breast cancer progression. Furthermore, integrin-linked kinase can 'convert' localized breast cancer cells into invasive and metastatic cells. Upon stimulation by growth factors and chemokine ligands, integrin-linked kinase mediates the phosphorylation of Akt Ser473, and glycogen synthase kinase-3. The current notion is that overexpression of integrin-linked kinase resulted in an invasive, metastatic phenotype in several cancer model systems in vivo and in vitro, thus, implicating a role for integrin-linked kinase in oncogenic transformation, angiogenesis and metastasis. Here, we will review the role of integrin-linked kinase in breast cancer metastasis. Elucidation of signalling events important for breast tumour metastasis should provide insights into successful breast cancer therapies.
 ...
PMID:Contributions of integrin-linked kinase to breast cancer metastasis and tumourigenesis. 1836 48

The chemotherapeutic agent methotrexate is widely used in the treatment of breast cancer. Although its mechanism-of-action has been defined, less is known about its interaction with T cell-mediated antitumor responses. Type 1 CD8 T cell-mediated immune responses (Tc1) are cytolytic, produce IFN-gamma and are associated with effective antitumor responses. Using a murine transgenic TCR tumor model, we show that single-dose treatment with methotrexate enhanced CD8-mediated type 1 antitumor responses when administered 3 days prior to Tc1 effector cell transfer. Co-treatment with methotrexate not only enhanced donor Tc1 cell accumulation and persistence at sites of primary tumor growth, but also promoted elevated levels of activated donor TIL cells. This markedly enhanced the appearance of endogenous differentiated (CD44(High)) CD8 tumor-infiltrating cells when compared to that of corresponding groups receiving either MTX or Tc1 cell transfer alone. Such cells were acutely activated as defined by co-expression of surface markers associated with TCR engagement (CD69) and T cell activation (CD25) at both early (days 1-8) and late (days 12-20) stages following treatment. Conversely, such animals showed an early decrease in CD4(+)/CD44(High)/CD25(+)/CD69(+) T cells that correlated with delays in tumor growth in vivo. Moreover, cellular response kinetics appeared to further correlate with the up-regulation of endogenous T cells producing the chemokine IP-10 in vivo. This suggested that Tc1 cell transfer, in combination with chemotherapy, can enhance antitumor responses by modulating immunoregulatory T cells involved in homeostasis and immune tolerance within the tumor environment. These studies offer insight into mechanisms that enhance T cell-based immunotherapy in cancer.
 ...
PMID:Ag-specific type 1 CD8 effector cells enhance methotrexate-mediated antitumor responses by modulating differentiated T cell localization, activation and chemokine production in established breast cancer. 1851 46

The chemokine receptor CXCR4 and its ligand CXCL12 play an important role in breast cancer invasion and metastasis, and induce the chemotaxis of various types of cancer cells. Previous studies of CXCL12-induced chemotaxis have, for the most part, relied on endpoint assays (e.g., transwell assays) that provide poor control over the cell microenvironment. Specifically, these assays lacked the ability to dissect the role that autocrine and paracrine growth factors play in chemokine-induced cancer cell chemotaxis. Here, we employ a microfluidic chemotaxis chamber that allows the effects of specific exogenous factors on cell migration to be directly characterized, without the interference of autocrine/paracrine signaling. Using this approach, we investigated the migration of MDA-MB-231 breast cancer cells in well-defined CXCL12 gradients. We found that CXCL12 alone failed to stimulate chemotaxis of these cells; however, when the CXCL12 gradient was supplemented with a uniform stimulus of either EGF or conditioned media, a directional response was induced. This dependence on growth factor signaling points to the importance of autocrine and paracrine factors in determining the migratory response of the cells, and may play an important role in cancer metastasis.
 ...
PMID:Epidermal growth factor promotes breast cancer cell chemotaxis in CXCL12 gradients. 1855 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>