Inflammation and breast cancer. Inflammatory component of mammary carcinogenesis in ErbB2 transgenic mice

Abstract

This review addresses genes differentially expressed in the mammary gland transcriptome during the progression of mammary carcinogenesis in BALB/c mice that are transgenic for the rat neu (ERBB2, or HER-2/neu) oncogene (BALB-neuT664V-E mice). The Ingenuity knowledge database was used to characterize four functional association networks whose hub genes are directly linked to inflammation (specifically, the genes encoding IL-1beta, tumour necrosis factor, interferon-gamma, and monocyte chemoattractant protein-1/CC chemokine ligand-2) and are increasingly expressed during such progression. In silico meta-analysis in a human breast cancer dataset suggests that proinflammatory activation in the mammary glands of these mice reflects a general pattern of human breast cancer.

Figure 1

Most significant Ingenuity functional classes found to be enriched in GATMs. GATM, gene associated with mammary tumour microenvironment.

Figure 2

Network of functional association between TNF gene and other GATMs generated by Ingenuity database analysis. RAET1B, KLRD1 and KLRK1 are genes associated with cytotoxicity; TNFRSF21 and AATK are genes involved in apoptosis. LITAF, AK2 and KLRC2 are genes associated with proliferation regulation. PLA2G7 is a gene associated with inflammatory response. All of the other genes have unknown cell functions. Genes are shown by their symbols [44]. The nodes represent the genes and the edges reflect direct links or connections between them. GATM, gene associated with mammary tumour microenvironment; TNF, tumour necrosis factor.

Figure 3

Network of functional association between IFN-γ gene and other GATMs generated by Ingenuity database analysis. ADIPOQ, CCL22, IFNG, IL1B, PPARA, RXRG, MSR1, GAD1 and TAP1 are genes associated with proliferation, whereas USP18 and CDH13 are genes linked to growth. ASS, DUSP5, ADCY5 and UBD are genes associated with apoptosis/survival. CXCR6, CXCL16 and CNR2 are genes associated with chemotaxis/trafficking; KLRK1 and HCST are associated with cytolysis/cytotoxicity; and RARRES1 and CD36 are linked to migration. All of the other genes have unknown cell functions. Genes are shown by their symbols. GATM, gene associated with mammary tumour microenvironment; IFN, interferon.

Figure 4

Network of functional relationships between IL-1β gene and other GATMs generated by Ingenuity database analysis. AIF1, CCL4, CCL5, CCL7, CXCL6, IL1B, NFKBIZ and PIGR are associated with the inflammatory response. All of the other genes have unknown cell functions. Genes are shown by their symbols. GATM, gene associated with mammary tumour microenvironment; IL, interleukin.

Figure 5

Network of functional association between CCL2 gene and other GATMs generated by Ingenuity database analysis. F3, F2R, F12, F10 and KNG1 are part of the complement and coagulation cascades. MMP12 encodes a matrix metalloproteinase involved in tissue remodelling. HBEGF and PGF encode growth factors. Associations with VEGF and KDR have been omitted for the sake of legibility. Genes are shown by their symbols. CCL, CC chemokine ligand; GATM, gene associated with mammary tumour microenvironment.

Figure 6

Clustering of expression of genes associated to inflammation. Shown is hierarchical clustering of gene-centred expression of the 65 genes present in the IFN-γ, TNF, IL-1β and MCP-1/CCL2 gene functional association networks. Samples from the dataset, presented by Chin and coworkers [38], cluster in three groups (A, B and C) if the expression levels of the proinflammatory genes are used. CCL, CC chemokine ligand; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; TNF, tumour necrosis factor.

Figure 7

Scatterplot of pair-wise correlation comparison within the probe sets in the two datasets. Integrative correlation coefficient [40] was used to quantify the extent of the similarity between the tumour specimens and breast cancer cell line transcription profiles. All pair-wise correlations (Pearson correlation coefficient) of gene expression across samples within individual projects were calculated, and the reproducibility of the results was defined without relying on direct comparison of expression across platforms.

Figure 8

Box-plot of the expression level distributions of the 65 GATMs presented by Chin and coworkers. The IFN-γ, TNF, IL-1β and MCP-1/CCL2 hub genes are shown in grey. The inset figure shows their expression levels within the intensity distribution of tumour dataset presented by Chin and coworkers [38]. CCL, CC chemokine ligand; GATM, gene associated with mammary tumour microenvironment; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; TNF, tumour necrosis factor.