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)

CD8 T cell-mediated immune responses fall into two distinct types based on effector cell-derived cytokine production. Type I CD8 T cells (Tc1) produce IFN-gamma, whereas type 2 cells (Tc2) secrete IL-4, IL-5, IL-10, and GM-CSF. Using a murine TCR transgenic T cell/breast tumor model, we show that adoptively transferred Ag-specific Tc1 cells are more effective in delaying mammary tumor growth and progression than that of functionally distinct Tc2 cells. Donor Tc1 cells administered 7 days posttumor challenge localized and persisted at sites of primary tumor growth with antitumor responses that were dependent, in part, on effector cell-derived IFN-gamma. Tc1-mediated responses markedly enhanced the appearance and local accumulation of highly differentiated (CD44(high)) CD4 and CD8 endogenous tumor-infiltrating T cells when compared with that of untreated tumor-bearing mice. Conversely, Tc1 cell transfer markedly delayed the appearance of corresponding nondifferentiated (CD44(low)) endogenous T cells. Such cells were acutely activated as defined by coexpression of surface markers associated with TCR engagement (CD69) and early T cell activation (CD25). Moreover, cellular response kinetics appeared to further correlate with the up-regulation of endogenous T cells producing the chemokine IFN-gamma-inducible protein-10 in vivo. This suggested that CD8-mediated type 1 antitumor responses cannot only promote accumulation of distinct endogenous CD4 and CD8 T cell subpopulations, but also facilitate and preferentially modulate their localization kinetics, persistence, states of activation/differentiation, and function within the primary tumor environment at various stages of tumor progression. These studies offer insight into potential mechanisms for enhancing T cell-based immunotherapy in breast cancer.
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PMID:CD8-mediated type 1 antitumor responses selectively modulate endogenous differentiated and nondifferentiated T cell localization, activation, and function in progressive breast cancer. 1711 96

The chemokine CXCL12, also known as stromal cell-derived factor-1 (SDF-1), is a small protein that regulates leukocyte trafficking and is variably expressed in a number of normal and cancer tissues. CXCL12 as ligand and its receptor CXCR4 have been implicated in colorectal cancer (CRC) progression including angiogenesis and metastasis. A CXCL12 gene variant CXCL12-A (CXCL12-G801A, a single nucleotide polymorphism in the 3' untranslated region) is associated with increased susceptibility to breast cancer. Based on the suggested role of CXCL12 in the pathogenesis of cancer we examined the association of the gene variant CXCL12-A with CRC. The polymorphism was analysed with PCR and RFLP methods. Furthermore, the plasma CXCL12 levels from patients with CRC were also examined. There was no significant difference in genotype distribution and allelic frequencies between CRC patients (n=151) and controls (n=141). On the other hand, we found that the carrying rate of allele CXCL12-A was higher in colon cancer patients compared with rectal cancer patients (P=0.017). Analyses by ELISA showed that CRC patients (n=63) had a lower CXCL12 plasma level compared with controls (P<0.0001). Moreover, patients with tumours classified as Dukes' stage B and C revealed lower levels than patients with tumours in Dukes' stage A. Further studies with larger samples of patients are necessary to determine whether the CXCL12 polymorphism and plasma level reflect the clinical outcome of CRC and have an impact on CRC progression.
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PMID:Polymorphism and circulating levels of the chemokine CXCL12 in colorectal cancer patients. 1714 42

Breast cancer cells preferentially spread to bone. Bone metastases are currently incurable and therefore better treatments need to be developed. Metastasis is an inefficient, multi-step process. Specific aspects of both breast cancer cells and the bone microenvironment contribute to the development of bone metastases. Breast cancers express chemokine receptors, integrins, cadherins, and bone-resorbing and bone-forming factors that contribute to the successful and preferential spread of tumor to bone. Bone is rich in growth factors and cell types that make it a hospitable environment for breast cancer growth. Once breast cancer cells enter the bone, a highly complex vicious cycle develops, in which breast cancer cells secrete factors that act on bone cells and other cells within the bone (stem cells, T cells, platelets, adipocytes, fibroblasts, and endothelial cells), causing them to secrete factors that act on adjacent cancer cells. The steps in the metastatic cascade and the vicious cycle within bone offer unique targets for adjuvant treatments to treat and cure bone metastases.
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PMID:Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases. 1716 31

Endothelin expression is increased in breast tumors and is associated with invasion and metastasis, whereas CCR7 expression by breast tumor cells may have a role in the organ specificity of breast cancer spread. In this article, we have analyzed whether endothelins influence breast tumor cell expression of the chemokine receptor CCR7. Stimulation of human breast tumor cell lines with endothelins increased cell surface expression of CCR7 via endothelin receptor A. The iron chelators desferrioxamine and cobalt chloride, which induce hypoxia-inducible factor (HIF)-mediated transcription, also increased CCR7 expression; transfection of a dominant-negative version of the HIF regulatory subunit, HIF-1alpha, into MCF-7 cells abolished CCR7 induction by endothelins, indicating that increased expression is due to HIF-1 stabilization. Endothelin stimulation promoted invasion toward the CCR7 ligands CCL19 and CCL21. Endothelin-mediated chemokine-independent invasion itself is dependent on CCR7 activity and could be abolished using a CCR7-neutralizing monoclonal antibody. In human breast carcinomas, mRNA expression of endothelins correlated with the level of CCR7 expression, both of which were associated with the presence of lymph node metastases. Expression of the CCR7 ligands CCL19 and CCL21 was also higher in breast cancer patients with lymph node involvement compared with those without, but expression of these chemokines did not correlate with endothelin expression. These data show that CCR7 may be regulated by the breast tumor microenvironment and further support the use of endothelin receptor antagonists in the treatment of invasive and metastatic breast cancer.
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PMID:Endothelins induce CCR7 expression by breast tumor cells via endothelin receptor A and hypoxia-inducible factor-1. 1728 12

HER2/neu overexpression is a driving force in the carcinogenesis of several human cancers. In breast cancer the prognostic influence of HER2/neu was shown to be at least partly based on increased metastatic potential mediated by the chemokine-chemokine receptor pair SDF-1(CXCL12)/CXCR4. We wanted to evaluate the influence of HER2/neu on ovarian cancer prognosis and to investigate whether compromised survival would correlate with CXCR4 expression and/or SDF-1 abundance. Therefore, we analysed HER2/neu, CXCR4, and SDF-1 in 148 ovarian tumour samples by means of immunohistochemistry on tissue microarrays. Overexpression of HER2/neu was found in 27.6% of ovarian cancer tissues and in 15% of ovarian borderline tumours. In ovarian cancer patients, overexpression of HER2/neu correlated closely with overall survival (univariate hazard ratio (HR) 2.59, P=0.005; multiple corrected HR 1.92, P=0.074). In contrast, CXCR4 expression and SDF-1 abundance had no impact on overall survival, and both parameters were not correlated with HER2/neu expression. As expected, cytoplasmic CXCR4 expression and SDF-1 abundance correlated closely (P<0.0001). Our results confirm a univariate influence of HER2/neu expression on overall survival, which was completely independent of the expression of CXCR4 and the abundance of SDF-1, implying significant differences between the HER2/neu downstream pathways in ovarian cancer compared with breast cancer.
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PMID:In ovarian cancer the prognostic influence of HER2/neu is not dependent on the CXCR4/SDF-1 signalling pathway. 1724 39

Human telomerase reverse transcriptase (TERT) has been considered a potential tumor-associated antigen for active-specific immunotherapy. However, effective specific tumor antigen-specific immunity has been difficult to induce consistently by various TERT vaccine formulations. New adjuvant strategies have been employed, such as utilizing chemokines to attract T cells and antigen-presenting cells. Chemokine adjuvant strategies may enhance tumor antigen-specific immunity induced by vaccines. Therefore, we utilized chemokine ligand 21 (CCL21) as an adjuvant with a xenogeneic TERT DNA vaccine to induce tumor antigen-specific immunity against TERT-expressing breast cancer. The TERT DNA vaccine consisted of a plasmid containing the COOH terminal end of the TERT (cTERT) gene, encapsulated in multilayered liposomes with hemagglutinating virus of Japan coating. We demonstrated that CCL21 treatment before cTERT DNA vaccine, given intramuscularly, induced significantly higher anti-TERT specific cell-mediated immunity compared to cTERT DNA vaccine alone. Effective tumor antigen-specific immunity was shown both in prophylactic and therapeutic regimens against TS/A murine breast cancer. The study demonstrated that CCL21 administration before cTERT DNA vaccination significantly augmented tumor antigen-specific immunity against breast cancer.
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PMID:Immunity against breast cancer by TERT DNA vaccine primed with chemokine CCL21. 1731 99

Increased risk for the development of endometrial cancer has been associated with unopposed oestrogen exposure, hyperoestrogenic factors, and a history of breast cancer treated long-term with tamoxifen (Tam). Stromal cell-derived factor-1, currently named as CXCL12, is a chemokine that, via binding to CXCR4 receptor, activates several downstream effectors and signalling pathways responsible for proliferation, survival, and migration of cancer cells. We observed that 17beta-estradiol (E2) and tamoxifen (Tam) increase the expression of CXCR4 and CXCL12 transcripts and proteins in oestrogen receptor positive (ER(+)) but not in negative (ER(-)02) Ishikawa endometrial adenocarcinoma (ISH) cell lines. However, the demethylating agent 5-Aza-2'-deoxycytidine profoundly elevated CXCR4 and CXCL12 expression in both ER(+) and ER(-)02 ISH cells. Bisulfite sequencing revealed that E2 and Tam up-regulate expression via demethylation of cytosine in the cytosine-guanosine dinucleotide island of CXCR4 and CXCL12 promoters. We also found that E2 and Tam significantly increased, for several hours, the expression of DNA methyltransferase 3B4 enzymatically inactive splice variant in ER(+) but not in ER(-)02 ISH cells. Our results suggest that E2 and Tam, through their ability for gene-transcription regulation, change the cellular milieu that maintains the hypermethylated stage of CpG islands of CXCR4 and CXCL12 promoters.
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PMID:Epigenetic up-regulation of CXCR4 and CXCL12 expression by 17 beta-estradiol and tamoxifen is associated with formation of DNA methyltransferase 3B4 splice variant in Ishikawa endometrial adenocarcinoma cells. 1736 37

Identification of genes/proteins that are differentially expressed in HER2 (erbB-2) oncogene-dependent breast carcinomas is essential in elucidating the mechanistic basis of their increased metastastic potential and resistance to several anti-cancer therapies. We here applied human cytokine antibody arrays with the goal of identifying a unique HER2-induced 'cytokine signature' in breast cancer. Human Cytokine Array III (RayBiotech, Inc.), which simultaneously detects 42 cytokines and growth factors on one membrane, was used to determine the profile of cytokines in conditioned media obtained from MCF-7/Her2-18 cells, a MCF-7-derived clone engineered to stably express the full-length human HER2 cDNA controlled by a SV40 viral promoter, and from the MCF-7/neo control sub-line. We identified two inflammatory and pro-angiogenic CXC chemokines with at least a 10-fold increased expression in HER2-overexpressing MCF-7/Her2-18 transfectants when compared to matched control MCF-7/neo cells: CXCL8 (IL-8; Interleukin-8) and CXCL1 and (GRO; Growth-related oncogene). HER2-induced differential overexpression of IL-8 and GRO was validated by ELISA and further confirmed by switching off the HER2 signalling. Treatment with the tyrosine kinase inhibitor gefitinib (Iressa) returned the expression levels of IL-8 and GRO back to the baseline observed in MCF-7 breast cancer cells, which express physiological levels of HER2. To evaluate the diagnostic utility of these findings, cytokine-specific antibody arrays were incubated with sera retrospectively collected from metastatic breast cancer patients. This approach revealed a high similarity between the 'cytokine signature' observed in serum samples and that obtained in media conditioned by breast cancer-derived cell lines. Thus, IL-8 and GRO circulating levels were significantly higher in HER2-positive breast cancer patients compared with HER2-negative patients. These findings reveal for the first time that: a) Enhanced synthesis and secretion of members of the IL-8/GRO chemokine family, which have recently been linked to oestrogen receptor (ER) inaction, increased cell invasion and angiogenesis, may represent a new pathway involved in the metastatic progression and endocrine resistance of HER2-overexpressing breast carcinomas, and b) Circulating levels of IL-8 and GRO cytokines may represent novel biomarkers monitoring breast cancer responses to endocrine treatments and/or HER2-targeted therapies.
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PMID:Protein array technology to detect HER2 (erbB-2)-induced 'cytokine signature' in breast cancer. 1737 3

Chemokines have been initially characterized as chemoattractants for leukocytes infiltrating into inflamed tissues. However, over the past few years, accumulating evidence has described the critical involvement of this superfamily of intercellular signaling proteins in a variety of biological processes, which include embryogenesis, organogenesis, and tissue homeostasis. Moreover, recent work has demonstrated novel roles for chemokines and their receptors in regulating various aspects of the transformed phenotype, such as tumor growth, angiogenesis, invasion, and metastasis. Here, we review the current knowledge regarding chemokine/chemokine receptor involvement in breast cancer pathogenesis with primary emphases on their role in the metastatic spread of cancer cells and in tumor-stroma interactions.
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PMID:Chemokine networks and breast cancer metastasis. 1747 67

Chemokines are small, secreted proteins and are now the largest known cytokine family. They mediate their effects through a family of G-protein-coupled receptors and were initially recognized for their ability to act as chemo-attractants and activators of specific types of leucocytes in a variety of immune and inflammatory responses. However, during the past 5 years there has been a chemokine revolution in cancer and all scientists and clinicians in oncology-related fields are now aware of their crucial role at all stages of neoplastic transformation and progression. The most important chemokine ligand-receptor interaction is that of the CXCL12 (stromal cell-derived factor-1, SDF-1) ligand with its exclusive receptor CXCR4; this interaction has a pivotal role in the directional migration of cancer cells during the metastatic process. This has been demonstrated by in vitro and in vivo experiments in addition to retrospective clinical studies. These findings have exciting implications in the field of cancer therapeutics, with several small molecule CXCR4 antagonists having been developed, which may provide clinical benefit in the therapy of cancer metastasis. Interestingly, it is likely that the effect of the anti-HER2 antibody [trastuzumab (Herceptin] in breast cancer involves downregulation of the CXCR4 receptor. Unfortunately, a major problem is that chemokine receptors are expressed in other cells within the body, particularly those of the immune system and it is not clear what effects long-term CXCR4 antagonism could have on innate and adaptive immunity. However, there is little doubt that the great strides made in elucidating the complex relationship between chemokines and their role in cancer will soon translate into significant survival benefits for patients.
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PMID:Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration. 1751 May 63


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