Overexpression of matrix metalloproteinases and their inhibitors in mononuclear inflammatory cells in breast cancer correlates with metastasis-relapse - PubMed (original) (raw)

Overexpression of matrix metalloproteinases and their inhibitors in mononuclear inflammatory cells in breast cancer correlates with metastasis-relapse

L O González et al. Br J Cancer. 2007.

Abstract

An immunohistochemical study was performed using tissue microarrays and specific antibodies against matrix metalloproteinase (MMP)-1, -2, -7, -9, -11, -13 and -14, tissular inhibitors of metalloproteinase (TIMP)-1, -2 and -3. More than 2600 determinations on cancer specimens from 131 patients with primary ductal invasive tumours of the breast were performed. To identify specific groups of tumours with distinct expression profiles the data were analysed by unsupervised hierarchical cluster analysis by each cellular type. We did not find well-defined cluster of cases for tumour cells or fibroblastic cells. However, for mononuclear inflammatory cells the dendogram shows a first-order division of the tumours into two distinct MMP/TIMP molecular profiles, designated group 1 (n=89) and group 2 (n=42). Matrix metalloproteinase-7, -9, -11, -13 and -14, and TIMP-1 and -2, were identified as showing significant high expression in group 2 compared with group 1. Multivariate analysis demonstrated that clustering for mononuclear inflammatory cells was the most potent independent factor associated with distant relapse-free survival (group 2: 5.6 (3.5-9.6), P<0.001). We identify a phenotype of mononuclear inflammatory cells infiltrating tumours, which is associated with the development of distant metastasis. Therefore, this finding suggests that these host inflammatory cells could be a possible target for inhibition of metastasis.

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Figures

Figure 1

Figure 1

Left: examples of tissue with immunostaining for the more significant proteins in patients with tumours belong to poor prognostic group (cluster 2 group: A, B and C) and better prognostic group (cluster 1 group: D, E and F; magnification × 400). (A) Immunohistochemical staining of matrix metalloproteinase (MMP)-11 in inflammatory mononuclear cells, tumour cells and fibroblastic cells. (B) Immunohistochemical staining of MMP-9 in inflammatory mononuclear cells, tumour cells and fibroblastic cell negatives. (C) Immunohistochemical staining of tissular inhibitors of metalloproteinase (TIMP)-1 in inflammatory mononuclear cells and in fibroblastic cells, tumour cell negatives. (D) No immunohistochemical staining of MMP-9 in inflammatory mononuclear cells, tumour cells and fibroblastic cells. (E) Immunohistochemical staining of MMP-11 in tumour cells, inflammatory mononuclear cells and fibroblastic cell negatives. (F) Immunohistochemical staining of TIMP-1 in fibroblastic cells, inflammatory mononuclear cells and tumour cell negatives. In all cases, inflammatory mononuclear cells are indicated with small arrows, and fibroblastic cells with large arrows.

Figure 2

Figure 2

Hierarchical clustering analysis of global matrix metalloproteinases (MMPs)/tissular inhibitors of metalloproteinases (TIMPs) expressions in the different cell types of breast cancer as measured by immunohistochemistry on tissue microarray (TMA). Graphical representation of hierarchical clustering results in tumour cells (A), fibroblasts (B) and mononuclear inflammatory cells (C). Rows, tumoural samples; columns, MMPs/TIMPs. Protein expressions are depicted according to a color scale: red, positive staining; green, negative staining; grey, missing data. No major clusters of tumours are shown in tumour cells and fibroblasts. Two major clusters of tumours (1 and 2) are shown in mononuclear inflammatory cells.

Figure 3

Figure 3

(A) Representative Western blots of immunoreactive matrix metalloproteinases (MMPs). (A) Eighty micrograms of cytosol extract from seven human breast carcinomas (lanes 2–8) were subject to 12% SDS–PAGE and transferred onto a nitrocellulose membrane and then immunolabelled with MMP-1, -11, -13, -14 and _β_-actin (used as loading control) antiserum. Lane 1, molecular weight marker (50 kDa). (B) Western blots of immunoreactive MMP-11 and _β_-actin (used as loading control) from two human breast carcinomas (lanes 1 and 2) and from human placenta (used as positive control, lane 3).

Figure 4

Figure 4

Kaplan–Meier survival curves as a function of the two major clusters of tumours (Groups 1 and 2) shown in mononuclear inflammatory cells.

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