CCL2/CCR2 Chemokine Signaling Coordinates Survival and Motility of Breast Cancer Cells through Smad3 Protein- and p42/44 Mitogen-activated Protein Kinase (MAPK)-dependent Mechanisms

Fang, Wei Bin; Jokar, Iman; Zou, An; Lambert, Diana; Dendukuri, Prasanthi; Cheng, Nikki

doi:10.1074/jbc.m112.365999

Cited by 175 publications

(173 citation statements)

References 93 publications

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“…All aforementioned stimuli were shown to promote cancer progression by enhancing cancer cell proliferation, migration, and invasion (32)(33)(34). Although TGF-␤1 and CCL2 increased cell surface expression of ENO-1 (Fig.…”

Section: Eno-1 Exteriorization Is Triggered By Stimuli Promotingmentioning

confidence: 99%

STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization

Didiášová

Zakrzewicz

Magdolen

et al. 2015

Journal of Biological Chemistry

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Background: Cell surface-associated enolase-1 regulates plasmin formation and thus pericellular proteolysis. Results: STIM1/ORAI1-mediated Ca 2ϩ influx controls enolase-1 exteriorization in cancer cells. Conclusion: Extracellular enolase-1 regulates migratory and invasive properties of cancer cells. Significance: Enhanced exteriorization of enolase-1 may aggravate the malignant behavior of cancer cells and thus contribute to metastasis formation.

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Section: Eno-1 Exteriorization Is Triggered By Stimuli Promotingmentioning

confidence: 99%

STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization

Didiášová

Zakrzewicz

Magdolen

et al. 2015

Journal of Biological Chemistry

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“…[27][28][29] CCL2 modulates macrophage recruitment to breast tumors and also signals to breast cancer cells to modulate tumor survival and invasion. [30][31][32][33] Antibody neutralization of CCL2 inhibits growth and invasion of breast tumor xenografts. [32][33][34] Previous studies have primarily examined CCL2 expression for its association with macrophages in breast cancer and patient prognosis and have reported different results.…”

mentioning

confidence: 99%

Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers

Yao

Staggs

et al. 2016

Modern Pathology

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Despite advances in treatment, up to 30% of breast cancer patients experience disease recurrence accompanied by more aggressive disease and poorer prognosis. Treatment of breast cancer is complicated by the presence of multiple breast cancer subtypes, including: luminal, Her2 overexpressing, and aggressive basal-like breast cancers. Identifying new biomarkers specific to breast cancer subtypes could enhance the prediction of patient prognosis and contribute to improved treatment strategies. The microenvironment influences breast cancer progression through expression of growth factors, angiogenic factors and other soluble proteins. In particular, chemokine C-C ligand 2 (CCL2) regulates macrophage recruitment to primary tumors and signals to cancer cells to promote breast tumor progression. Here we employed a software-based approach to evaluate the prognostic significance of CCL2 protein expression in breast cancer subtypes in relation to its expression in the epithelium or stroma or in relation to fibroblast-specific protein 1 (Fsp1), a mesenchymal marker. Immunohistochemistry analysis of tissue microarrays revealed that CCL2 significantly correlated with Fsp1 expression in the stroma and tumor epithelium of invasive ductal carcinoma. In the overall cohort of invasive ductal carcinomas (n = 427), CCL2 and Fsp1 expression in whole tissues, stroma and epithelium were inversely associated with cancer stage and tumor size. When factoring in molecular subtype, stromal CCL2 was observed to be most highly expressed in basal-like breast cancers. By Cox regression modeling, stromal CCL2, but not epithelial CCL2, expression was significantly associated with decreased recurrence-free survival. Furthermore, stromal CCL2 (HR = 7.51 P = 0.007) was associated with a greater hazard than cancer stage (HR = 2.45, P = 0.048) in multivariate analysis. These studies indicate that stromal CCL2 is associated with decreased recurrence-free survival in patients with basal-like breast cancer, with important implications on the use of stromal markers for predicting patient prognosis.

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“…MCP-1 is expressed at relatively low levels in normal mammary epithelial tissue and circulating plasma, but increases dramatically with breast cancer progression. 13,[33][34][35] Recently, MCP-1 has been shown to signal to breast cancer cells to regulate survival and invasion, 14 promote primary tumor growth, 15 and mediate breast cancer metastasis. 36 Interestingly, TNBC educated macrophages secrete higher amounts of MCP-1 than macrophages co-cultered with estrogen receptor positive breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…11 In mammary tumors, overexpression of MCP-1 correlates with increased recruitment of macrophages and infiltration into the tumor environment that can facilitate tumor progression through macrophage-mediated angiogenesis 12 and through secretion of growth and survival factors. 13 Recent studies demonstrate that MCP-1 also signals to breast cancer cells to regulate survival and invasion 14 as well as promote primary tumor growth. 15 While these reports indicate that MCP-1 can regulate multiple mechanisms involved in breast cancer progression, its role in TNBC has not yet been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model

Cranford

Velázquez

Enos

et al. 2017

Cancer Biology & Therapy

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Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFa and IL-1b) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators.

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CCL2/CCR2 Chemokine Signaling Coordinates Survival and Motility of Breast Cancer Cells through Smad3 Protein- and p42/44 Mitogen-activated Protein Kinase (MAPK)-dependent Mechanisms

Cited by 175 publications

References 93 publications

STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization

STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization

Elevated expression of chemokine C-C ligand 2 in stroma is associated with recurrent basal-like breast cancers

Loss of monocyte chemoattractant protein-1 expression delays mammary tumorigenesis and reduces localized inflammation in the C3(1)/SV40Tag triple negative breast cancer model

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