Fig 1.
(A) Representative microphotographs revealing (left top) negative, (right top) weak, (left bottom) moderate and (right bottom) strong intensity MMP-11 expression using immunohistochemical staining (original magnification × 400). (B) HUGH cohort: High MMP-11 expression was associated with poor disease-free survival (left) and disease-specific survival (right) in 226 patients (p = 0.05 and 0.044, respectively). (C) TCGA: High MMP-11 expression in primary tumors compared to that in normal tissues. (D) TCGA: High MMP-11 expression was associated with poor disease-free survival (left) and disease-specific survival (right) in 776 patients in TCGA (p = 0.033 and 0.028, respectively).
Table 1.
Clinicopathological parameters of MMP-11 in patient with invasive ductal carcinoma of the breast from HUGH cohort.
Table 2.
Disease-free and disease-specific survival analyses according to MMP-11 in 226 breast cancer patients (HUGH cohort).
Fig 2.
TCGA data (A) Gene set enrichment analysis of three MMP-11-dependent immunologic gene sets reveals the downregulation of CD8+ T cells, CD4+ T cells and B cells. (B) Bar plots of MMP-11 expression and the following parameters: (B) cancer testis antigen, activated dendritic cells, tumor-infiltrating lymphocytes, (C) CD8+ T cells, CD4+ memory T cells, and memory B cells.
Fig 3.
HUGH cohort (A) Representative microphotographs showing tumor-infiltrating CD8 T cells (brown): decreased CD8+ T cells (left top) in high MMP-11 expression (left bottom) and increased CD8+ T cells (right top) in low MMP-11 expression (right bottom) (original magnification × 400). (B) Bar plot of CD8 T cells (left) and CD4 T cells (right) per high-power field (× 400) (p = 0.024 and 0.045).
Fig 4.
Grouping of networks based on functionally enriched GO terms and pathways using Cytoscape software (version 3.8.0) and ClueGO application (version 2.5.6) (https://cytoscape.org/): Functionally grouped networks are linked to their biological function, and only the most significant term of the group is labeled.
MMP-11 is directly linked to collagen catabolic processes, collagen fibril organization and basement membrane organization, while it indirectly negatively regulates leukocyte differentiation and immune effector process. The specific hub genes directly or indirectly linked to MMP-11 included MTOR, PIK3CA, JAK2 and JAK3.
Fig 5.
Genomics of Drug Sensitivity in Cancer (GDSC) database analysis: (A) Pearson’s correlation analysis showing the natural log of the half-maximal inhibitory concentration (LN IC50) values of pictilisib and AZ960 in breast cancer cells (blue, low MMP-11 expression; red, high MMP-11 expression) (left). Bar plot showing the LN IC50 values of pictilisib and AZ960 in breast cancer cell lines with low (gray) and high (green) MMP-11 expression (p = 0.026 and 0.009, respectively) (error bars: Standard errors of the mean) (right).