Protein array technology to detect HER2 (erbB-2)-induced 'cytokine signature' in breast cancer

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.     

CCL18介导肿瘤微环境趋化因子网络导致卵巢癌不良预后的研究

目的 分析血清CC趋化因子配体18（CC-chemokine ligand 18,CCL18）与卵巢癌预后的关系及其对卵巢癌微环境中其他趋化因子及受体的调控作用,探讨CCL18促进肿瘤生长和转移的可能机制。方法 采用流式荧光微球法检测320例卵巢癌患者、150例盆腔良性肿块患者及100名正常对照女性血清样本中CCL18的表达,分析基因表达谱（Gene Expression Omnibus,GEO）以及癌症基因图谱（The Cancer Genome Atlas,TCGA）数据库中CCL18基因表达与卵巢癌患者预后的关系。采用过表达CCL18的卵巢上皮癌细胞SKOV3-GFP-CCL18建立裸鼠皮下移植瘤模型,实时荧光定量PCR（qRT-PCR）检测移植瘤内其他趋化因子及受体的表达。结果 卵巢癌患者血清中CCL18的表达水平显著高于盆腔良性肿块患者和正常对照女性 ［（238.04±93.59） ng/mL vs （94.36±59.17） ng/mL,P<0.001;（238.04±93.59） ng/mL vs（31.68±26.10） ng/mL,P<0.001］,且高表达CCL18的卵巢癌患者中位无疾病进展生存期较低表达者短（15.0 个月 vs 18.2个月,HR=1.25,95%CI：1.08~1.44,P=0.003）。CCL18激活卵巢癌微环境的XCL1-XCR1、XCL2-XCR1、CCL2-CCR2、CCL11-CCR3、CCL17-CCR4、CXCL9-CXCR3、CXCL11-CXCR3、CXCL12-CXCR4趋化因子-受体轴表达,抑制了CXCL1-CXCR2、CXCL6-CXCR2、CXCL8-CXCR2、CCL5-CCR1、CCL5-CCR5、CCL27-CCR10、CCL28-CCR10趋化因子-受体轴的表达。结论 CCL18促进卵巢癌细胞转移可能与激活转移趋化因子-受体XCL1-XCR1、XCL2-XCR1、CCL2-CCR2、CCL17-CCR4表达和下调CCL5-CCR5、CCL27-CCR10和CCL28-CCR10表达有关,其可能造成卵巢癌患者不良预后。     

Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells

Impaired PTEN function is a genetic hallmark of aggressive prostate cancers (CaP) and is associated with increased CXCL8 expression and signaling. The current aim was to further characterize biological responses and mechanisms underpinning CXCL8-promoted progression of PTEN-depleted prostate cancer, focusing on characterizing the potential interplay between CXCL8 and other disease-promoting chemokines resident within the prostate tumor microenvironment. Autocrine CXCL8-stimulation (i) increased expression of CXCR1 and CXCR2 in PTEN-deficient CaP cells suggesting a self-potentiating signaling axis and (ii) induced expression of CXCR4 and CCR2 in PTEN-wild-type and PTEN-depleted CaP cells. In contrast, paracrine CXCL8 signaling induced expression and secretion of the chemokines CCL2 and CXCL12 from prostate stromal WPMY-1 fibroblasts and monocytic macrophage-like THP-1 cells. In vitro studies demonstrated functional co-operation of tumor-derived CXCL8 with stromal-derived chemokines. CXCL12-induced migration of PC3 cells and CCL2-induced proliferation of prostate cancer cells were dependent upon intrinsic CXCL8 signaling within the prostate cancer cells. For example, in co-culture experiments, CXCL12/CXCR4 signaling but not CCL2/CCR2 signaling supported fibroblast-mediated migration of PC3 cells while CXCL12/CXCR4 and CCL2/CCR2 signaling underpinned monocyte-enhanced migration of PC3 cells. Combined inhibition of both CXCL8 and CXCL12 signaling was more effective in inhibiting fibroblast-promoted cell motility while repression of CXCL8 attenuated CCL2-promoted proliferation of prostate cancer cells. We conclude that tumor-derived CXCL8 signaling from PTEN-deficient tumor cells increases the sensitivity and responsiveness of CaP cells to stromal chemokines by concurrently upregulating receptor expression in cancer cells and inducing stromal chemokine synthesis. Combined chemokine targeting may be required to inhibit their multi-faceted actions in promoting the invasion and proliferation of aggressive CaP.     

Recruitment and activation of natural killer cells in vitro by a human dendritic cell vaccine

Recruitment of circulating natural killer (NK) cells into inflamed lymph nodes is known to provide a potent, IFN-gamma-dependent boost for Th1-polarized immune responses in mouse models. Such NK cell recruitment into draining lymph nodes is induced by certain s.c. injected adjuvants, including mature vaccine dendritic cells (DC), and is mediated by a CXCR3-dependent pathway. Here, we show that monocyte-derived immature human DCs stimulated with polyinosinic acid:polycytidylic acid, IFN-alpha, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IFN-gamma, alpha-type 1-polarized DC (alpha DC1), secrete profuse amounts of the CXCR3 ligand CXCL9/MIG and substantial amounts of CXCL10/IP-10 and CXCL11/I-TAC after withdrawal of maturation stimuli. In sharp contrast, no measurable production of these chemokines was found in DCs after maturation with the current gold standard maturation cocktail for human DC-based cancer vaccines consisting of TNF-alpha, IL-1 beta, IL-6, and prostaglandin-E(2) (PGE(2)-DC). PGE(2)-DCs preferentially produced the Th2 and regulatory T-cell-attracting chemokines CCL17/TARC and CCL22/MDC, whereas only marginal levels of these chemokines were produced by alpha DC1s. Functional studies in vitro showed that supernatants from mature alpha DC1s actively recruited CD3(-)CD56(+) NK cells and that adding anti-CXCL9/MIG antibodies to the alpha DC1 supernatant substantially reduced this recruitment. Finally, alpha DC1s were able to induce IFN-gamma production when cocultured with resting autologous NK cells, but only if concurrent CD40 ligation was provided. These novel findings indicate that injected human alpha DC1-based vaccines have the potential to recruit and activate NK cells during their arrival to draining lymph nodes and that this feature may be of relevance for efficient priming of Th1 cells and CTLs.     

Chemokine and chemokine receptor related to cancer metastasis

The relationship has become clear between the expression of chemokine/chemokine receptors on cancer cells and the invasion, metastasis and peritoneal dissemination. Many cancer cells express chemokine receptors which are not expressed on the surface of normal tissues. Recently, it has been reported that overexpression of CXCR4/CXCL12 is related with metastasis to lung, liver, lymph nodes and bone marrow, while the overexpression of CCR7/CCL21 is mainly related with lymph node metastasis. We performed a comparative analysis of differential gene expressions related to chemokines/chemokine receptors, and cytokines in established gastric cancer cell lines by cDNA microarray. Upregulated chemokine genes were CCL21, CCL5, CXCL14, CCL2, CXCL1, CXCL8, CXCL7 and CXCL12, which the downregulated chemokines genes were MIP-1alpha and TECK. The upregulated gene of chemokine receptors was CCR-6. In the cancer microenvironment, cancer cells readily formed edematous and inflammatory conditions, easily metastasizing to other organs with the suppression of dendritic cells. The chemokines/chemokine receptors will hopefully become the new targets for cancer therapies for the regulation of metastasis.     

The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells

Constitutive expression of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is characteristic of malignant ovarian surface epithelium. We investigated the hypothesis that this autocrine action of TNF-alpha generates and sustains a network of other mediators that promote peritoneal cancer growth and spread. When compared with two ovarian cancer cell lines that did not make TNF-alpha, constitutive production of TNF-alpha was associated with greater release of the chemokines CCL2 and CXCL12, the cytokines interleukin-6 (IL-6) and macrophage migration-inhibitory factor (MIF), and the angiogenic factor vascular endothelial growth factor (VEGF). TNF-alpha production was associated also with increased peritoneal dissemination when the ovarian cancer cells were xenografted. We next used RNA interference to generate stable knockdown of TNF-alpha in ovarian cancer cells. Production of CCL2, CXCL12, VEGF, IL-6, and MIF was decreased significantly in these cells compared with wild-type or mock-transfected cells, but in vitro growth rates were unaltered. Tumor growth and dissemination in vivo were significantly reduced when stable knockdown of TNF-alpha was achieved. Tumors derived from TNF-alpha knockdown cells were noninvasive and well circumscribed and showed high levels of apoptosis, even in the smallest deposits. This was reflected in reduced vascularization of TNF-alpha knockdown tumors. Furthermore, culture supernatants from such cells failed to stimulate endothelial cell growth in vitro. We conclude that autocrine production of TNF-alpha by ovarian cancer cells stimulates a constitutive network of other cytokines, angiogenic factors, and chemokines that may act in an autocrine/paracrine manner to promote colonization of the peritoneum and neovascularization of developing tumor deposits.     

TIRAP对上皮性卵巢癌细胞增殖和凋亡能力的影响

目的:研究TIRAP在上皮性卵巢癌细胞中的表达情况,及其对上皮性卵巢癌细胞增殖和凋亡能力的影响。方法:通过实时荧光定量PCR（qRT-PCR）和Western blot检测各组细胞中TIRAP的表达。利用CCK-8法、流式细胞技术探究TIRAP的表达对人上皮性卵巢癌细胞增殖和凋亡的影响。利用Western blot、ELISA法探究TIRAP的表达对p-NF-κB p65及下游免疫分子IL-6、TNF-α水平的影响。结果:与正常卵上皮细胞（IOSE-80）相比,上皮性卵巢癌细胞（SKOV-3,OVCAR3,A2780）中TIRAP的mRNA和蛋白表达显著升高。转染TIRAP siRNA 后,SKOV-3细胞中TIRAP的表达显著降低;CCK-8实验显示:转染培养第96 h时,si-TIRAP组OD值（1.85±0.06）较Blank组（2.42±0.16）及Scramble control组（2.50±0.10）明显降低;细胞凋亡检测显示:si-TIRAP组凋亡率明显高于对照组;Western blot实验显示:LPS+si-TIRAP组p-NF-κB p65的表达与对照组相比显著降低;ELISA实验显示:LPS+si-TIRAP组IL-6、TNF-α的含量与对照组相比显著下降。结论:TIRAP在上皮性卵巢癌细胞中的表达升高,可能是上皮性卵巢癌细胞增殖的机制之一;下调TIRAP的表达可以抑制上皮性卵巢癌细胞增殖,促进细胞凋亡,并且通过抑制NF-κB通路的活化降低其下游免疫分子的表达。     

Chemokine-protease interactions in cancer

Solid tumour and leukemic cells expressing chemokine receptors, metastasize to chemokine-secreting organs. Chemokines indirectly affect tumour development by attracting immunocompetent cells with pro- or anti-tumoral activities. Various membrane-associated and soluble proteases selectively cleave specific chemokines. Precursor plasma chemokines (CXCL7, CCL14) need to be proteolytically processed to obtain receptor affinity. Angiogenic CXC chemokines (CXCL1, CXCL8) have increased CXCR1/CXCR2 affinity after limited NH2-terminal processing, whereas truncated angiostatic chemokines (CXCL10) show lower CXCR3 affinity without loss of angiostatic potential. NH2-terminally cleaved monocyte chemotactic proteins (CCL2, CCL7, CCL8) have impaired capacity to attract tumour-associated macrophages and function as receptor antagonists for intact CC chemokines. Migration of Th1/CCR5+ and Th2/CCR4+ effector lymphocytes toward CCR5 (CCL5, CCL3L1) and CCR4 (CCL22) ligands is affected by cleavage. Although proteolytical processing of chemokines is well studied in vitro, the direct or indirect effects on tumour invasion and metastasis are only poorly evaluated.     

Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9‐genome editing promotes antitumor immunity and suppresses ovarian cancer progression

Programmed cell death ligand 1 (PD‐L1) on tumor cells suppresses anti‐tumor immunity and has an unfavorable prognostic impact in ovarian cancer patients. We herein report the pathophysiological and therapeutic impacts of PD‐L1 disruption in ovarian cancer. PD‐L1 was genetically disrupted in the murine ovarian cancer cell line ID8 using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9‐mediated genome editing. PD‐L1 knockout (KO) and control ovarian cancer cells were intraperitoneally inoculated into syngeneic mice, and survival and tumor dissemination were evaluated. Survival times were significantly longer in the PD‐L1‐KO ID8‐inoculated groups than in their control groups, and its therapeutic benefit was enhanced in combination with the cisplatin treatment. Tumor weights and ascites volumes were significantly lower in the PD‐L1‐KO ID8 groups than in their control groups. Immunohistochemical and immunofluorescence analyses showed that intratumoral CD4⁺ T cells, CD8⁺ T cells, NK cells and CD11c⁺ M1 macrophages were significantly increased, whereas regulatory T cells were significantly decreased in the PD‐L1‐KO ID8 groups compared with those in their control groups. The intratumoral mRNA expression of interferon‐γ, tumor‐necrosis factor‐α, interleukin (IL)‐2, IL‐12a, CXCL9 and CXCL10 was significantly stronger, while that of IL‐10, vascular endothelial growth factor, CXCL1 and CXCL2 was significantly weaker in the PD‐L1‐KO ID8 groups. These results indicate that CRISPR/Cas9‐mediated PD‐L1 disruption on tumor cells promotes anti‐tumor immunity by increasing tumor‐infiltrating lymphocytes and modulating cytokine/chemokine profiles within the tumor microenvironment, thereby suppressing ovarian cancer progression. These results suggest that PD‐L1‐targeted therapy by genome editing may be a novel therapeutic strategy for ovarian cancer.     

Interleukin 8: an autocrine growth factor for human ovarian cancer

We determined whether interleukin-8 (IL-8) plays a direct role in the progressive growth of ovarian cancer cells by isolating high- and low-IL-8-producing clones from the parental Hey-A8 human ovarian cancer cell line and compared their proliferative activity and tumorigenicity in nude mice. The effect of exogenous IL-8 and mouse antihuman IL-8 neutralizing antibody on ovarian cancer cell proliferation was investigated. Finally, we studied the modulation of IL-8 production in ovarian cancer cells by sense and antisense IL-8 expression vector transfection and its effect on proliferation. The Hey-A8(H) clone was selected for its overexpression of IL-8. It has a significantly higher proliferation rate than the low-IL-8-producing clone, Hey-A8(L). Recombinant IL-8 (50 ng/ml) caused a significant increase in proliferation of Hey-A8(L) clones, and 10 microg/ml neutralizing antibody against IL-8 significantly decreased proliferative activity of both Hey-A8(H) and Hey-A8(L) clones. Enforced IL-8 expression by IL-8 expression vector transfection in Hey-A8(L) clones significantly increased tumor cell proliferation, microvessel density, and hence, tumorigenicity. We conclude that IL-8 has a direct and indirect growth-potentiating activity in human ovarian cancer cells.     

Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers

Ovarian cancer is associated with a leukocyte infiltrate and high levels of chemokines such as CCL2. We tested the hypothesis that CCL2 inhibition can enhance chemotherapy with carboplatin and paclitaxel. Elevated CCL2 expression was found in three non‐MDR paclitaxel resistant ovarian cancer lines ES‐2/TP, MES‐OV/TP and OVCAR‐3/TP, compared to parental cells. Mice xenografted with these cells were treated with the anti‐human CCL2 antibody CNTO 888 and the anti‐mouse MCP‐1 antibody C1142, with and without paclitaxel or carboplatin. Our results show an additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. This therapeutic effect was largely due to inhibition of mouse stromal CCL2. We show that inhibition of CCL2 can enhance paclitaxel and carboplatin therapy of ovarian cancer.     

Chemokines in human colorectal carcinoma

BACKGROUND: Chemokines (CKs) may promote antitumor immunity in cancer, act as tumor growth factors, influence metastatic spreading or angiogenesis. The purpose of this study was to investigate whether CK expression is altered in colorectal carcinomas compared to normal mucosa and to elucidate its possible clinico-pathological implications. MATERIALS AND METHODS: The levels of CCL2 (MCP-1), CCL4 (MIP-1beta), CCL5 (RANTES), CXCL 1 (GRO-alpha), CXCL 5 (ENA-78) and CXCL 8 (IL-8) were investigated in 10 colorectal carcinomas and their corresponding normal mucosa by the use of ELISA. RESULTS: All CK analyzed, with the exception of CCL5 (RANTES), were expressed at a significantly higher level in malignant tissue. CONCLUSION: Therapeutic studies in colon carcinomas should, therefore, focus more on the neutralization of CKs than on their application.     

Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

Background

The inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNFα & IL-1β were shown to contribute to breast cancer development and metastasis. In this study, we wished to determine whether there are associations between these factors along stages of breast cancer progression, and to identify the possible implications of these factors to disease course.

Methods

The expression of CCL2, CCL5, TNFα and IL-1β was determined by immunohistochemistry in patients diagnosed with: (1) Benign breast disorders (=healthy individuals); (2) Ductal Carcinoma In Situ (DCIS); (3) Invasive Ducal Carcinoma without relapse (IDC-no-relapse); (4) IDC-with-relapse. Based on the results obtained, breast tumor cells were stimulated by the inflammatory cytokines, and epithelial-to-mesenchymal transition (EMT) was determined by flow cytometry, confocal analyses and adhesion, migration and invasion experiments.

Results

CCL2, CCL5, TNFα and IL-1β were expressed at very low incidence in normal breast epithelial cells, but their incidence was significantly elevated in tumor cells of the three groups of cancer patients. Significant associations were found between CCL2 & CCL5 and TNFα & IL-1β in the tumor cells in DCIS and IDC-no-relapse patients. In the IDC-with-relapse group, the expression of CCL2 & CCL5 was accompanied by further elevated incidence of TNFα & IL-1β expression. These results suggest progression-related roles for TNFα and IL-1β in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNFα and IL-1β compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNFα (and to some extent IL-1β) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1β acts jointly with other pro-malignancy factors to promote disease relapse.

Conclusions

Our findings suggest that the coordinated expression of CCL2 & CCL5 and TNFα & IL-1β may be important for disease course, and that TNFα & IL-1β may promote disease relapse. Further in vitro and in vivo studies are needed for determination of the joint powers of the four factors in breast cancer, as well as analyses of their combined targeting in breast cancer.     

Characterization of GRO alpha, beta and gamma expression in human colonic tumours: potential significance of cytokine involvement.

The GRO genes, isolated from transformed fibroblasts, belong to a superfamily of genes such as platelet factor 4 and neutrophil activating peptide/IL-8. Three related GRO genes are described which are closely linked on chromosome 4: GRO alpha, GRO beta, and GRO gamma: GRO beta and GRO gamma share 90 and 86% sequence homology with GRO alpha. The GRO alpha gene product shares homology with, and is melanocyte growth stimulatory activity (MGSA). The MGSA/GRO alpha has potent chemotactic, growth regulatory and transformative functions. The function of GRO beta and gamma is unknown. Expression of GRO alpha is well characterized in vitro; studies in actual human tissues are not reported. We chose to determine the specific expression of GRO alpha, beta and gamma in both normal and transformed human colonic tissues and to assess the role of exogenous cytokines on their induction. Tissues from ten patients with colonic neoplasia were obtained at the time of colectomy. All specimens underwent Northern analysis for GRO gene expression, comparing normal colonic mucosa with neoplastic mucosa. Differential GRO alpha, beta and gamma expressions were determined by polymerase chain reaction (PCR). GRO alpha expression was evaluated in the tumour specimens compared with normal, while there was constitutive expression of GRO gamma in both normal and neoplastic colonic mucosa. Expression of GRO beta was minimal in all tissue specimens. In addition, HT29 colon carcinoma cells stimulated with IL-1 beta and TNF alpha demonstrated induction of GRO alpha and IL-8. Thus, GRO alpha is differently elevated in in vivo colon carcinoma specimens. GRO gamma was constitutively expressed in colonic tissues; GRO beta was not similarly expressed.     

Biochemical composition of malignant ascites determines high aggressiveness of undifferentiated ovarian tumors

Although undifferentiated tumors are the most lethal among all ovarian cancer histotypes, the exact reasons for this situation are unclear. This report was aimed at investigating whether the high aggressiveness of undifferentiated ovarian cancer may be associated with a biochemical composition of malignant ascites accumulating in the peritoneal cavity. We analyzed ascites from patients with undifferentiated, high-grade serous, endometrioid and clear-cell ovarian cancers, and from non-cancerous patients with respect to a group of soluble agents involved in cancer cell progression. Moreover, the effect of these fluids on proliferation and migration of ovarian cancer cells (A2780, OVCAR-3 and SKOV-3) was evaluated. The study showed that the level of all tested proteins in malignant ascites was higher than in the benign fluids. Concentration of 9/11 agents (CCL2, CXCL1, CXCL5, CXCL8, CXCL12, HGF, PAI-1, TGF-β1 and VEGF) was the greatest in the fluids from undifferentiated cancer, while the level of remaining 2 (IL-6 and uPA) was the highest in ascites from serous carcinoma. Proliferation of cancer cells was the most effective when they were subjected to ascites from patients with undifferentiated and serous cancer, whereas the migration was the highest in the case of undifferentiated tumors. Our findings indicate that the aggressiveness of undifferentiated ovarian tumors may be associated with the composition of malignant ascites, in particular the concentration of specific proinflammatory, cancer-promoting agents.     

Expression Pattern and Prognostic Significance of Chemokines in Breast cancer: An Integrated Bioinformatics Analysis

BackgroundBreast cancer (BC), one of the most prevalent malignancies, is the second major cause of mortality from cancer among women worldwide. Even though substantial progress has been made in breast cancer treatment, metastasis still accounts for the majority of the deaths. The tumor microenvironment (TME) comprising stromal and non-stromal components is central to tumor growth and development and is partly regulated by chemokines. Chemokines regulate immune cell trafficking, the development of stroma and play a key role in inflammation, a cancer hallmark.MethodsIn the present study, we used a bioinformatics approach to identify highly deregulated chemokines in BC patients. We performed expression analysis, survival analysis, gene ontology analysis, KEGG analysis, and protein-protein interaction network analysis of the deregulated chemokines using Gepia2, UALCAN, Kaplan-Meier Plotter, DAVID, and STRING tools.ResultsWe identified >2-fold change (FC) increase in CXCL9/10/11/13 and >-2 FC decrease in CCL14/21/28, CXCL2/12 CX3CL1. Also, increased expression of CCL14, CCL21, CXCL13, CXCL9, CXCL12 correlated with better overall survival (OS) of BC patients.ConclusionsOur results strongly indicate that chemokines may have potential biomarker characteristics, and the constructed PPI network contributed to an in-depth understanding of the chemokine networks. The deregulated chemokines may prove to be therapeutic targets for the effective management of BC.