The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets

Palacios-Arreola, Margarita Isabel; Nava-Castro, Karen Elizabeth; Castro, Julieta Ivonne; García‐Zepeda, Eduardo A.; Carrero, Julio César; Morales‐Montor, Jorge

doi:10.1155/2014/849720

Cited by 70 publications

(60 citation statements)

References 54 publications

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“…33 The concomitant high expression of PD-1 ligands in these tumors, as supported by in situ evaluation of their expression in tumor specimens of HER2+ BCs that showed higher PD-L1 and PD-L2 positivity in TRAR-low compared to TRAR-high tumors, may represent one of the mechanisms exploited by tumors cells to evade immune control. Unlike the situation in patients with melanoma, in whom PD-L1 expression was described as being a negative feedback mechanism that followed CD8+ T cell infiltration and depended on their presence 34,35 the modulation of PD-1 ligands by HER2 signals that we demonstrated in BC cell lines suggests that in HER2+ BCs this immunosuppressive pathway is also directly orchestrated by cancer cells (i.e., innate immune evasion).…”

Section: Discussionmentioning

confidence: 87%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway.Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.

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Section: Discussionmentioning

confidence: 87%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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“…It is reported that KV7.3 is expressed in osteoblast‐like cells and plays an important role in osteoblast differentiation through glutamatergic communication during matrix maturation and mineralization . Nabeshima et al and Krieger et al found that inhibitory mutant chemokines and antagonists of chemokine receptors promoted osteoblast differentiation, bone metastasis and bone formation . In addition, chemokines produced by the osteoblasts mediate the crosstalk between osteoblasts and osteoclasts to maintain bone remodelling .…”

Section: Discussionmentioning

confidence: 99%

The molecular mechanism study of insulin on proliferation and differentiation of osteoblasts under high glucose conditions

Zhang

Jiang

Bai

et al. 2019

Cell Biochemistry & Function

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To explore the molecular mechanism of insulin on proliferation and differentiation of MC3T3‐E1 cell under high glucose conditions. We first investigated the effect of different concentrations of insulin on the osteoblast cell proliferation and cell differentiation at various time points by MTT analysis, cell cycle analysis, and expression detection of differentiation genes. Then, we used 200 ng/mL of insulin to treat the osteoblast cell at different time points for identifying the common differentially expressed mRNAs among various time points by RNA sequencing. Thirdly, we performed the gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis to explore the biological function of these common differentially expressed mRNAs. The results showed that insulin promoted the cell proliferation and differentiation of osteoblast cell. In RNA sequencing, a total of 31 common differentially expressed mRNAs were identified between different time points. Mt1, Tmem135, Avp, and Dlg2 were found to be associated with the new bone formation. In addition, three important signalling pathways, namely, lysosome, glutamatergic synapse, and chemokine signalling pathways, were found in the KEGG enrichment analysis. Our work demonstrated that insulin could promote the osteoblast cell proliferation and cell differentiation, which may play a key role in bone formation. Significance of the study Our result showed that insulin could promote the proliferation and differentiation of osteoblast at both cellular and molecular levels, which may promote the new bone formation in the osteoblasts.

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“…These interactions are often mediated by chemokines and their receptors, many of which belong to the G-protein-coupled receptor (GPCR) family of receptors (2). In tumors, local production of chemokines plays an important role in attracting leukocytes and other inflammatory cells (3). Similarly, tumor cells express receptors that respond to chemokines secreted by stromal cells, tumor-associated macrophages, tumor-infiltrating leukocytes, as well as chemokines secreted by adjacent tumor cells or in an autocrine manner (2).…”

Section: Introductionmentioning

confidence: 99%

GPCR Signaling Mediates Tumor Metastasis via PI3Kβ

et al. 2016

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Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Kα, a role for PI3Kβ has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein-coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolished PI3Kβ binding to Gβγ (p110526KK-DD). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCR and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease.

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The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets

Cited by 70 publications

References 54 publications

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

The molecular mechanism study of insulin on proliferation and differentiation of osteoblasts under high glucose conditions

GPCR Signaling Mediates Tumor Metastasis via PI3Kβ

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