MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: correlations with prognostic factors

Abstract

The matrix metalloproteinases (MMPs) are a family of structurally and functionally related proteinases, initially characterized by their ability to degrade the extracellular matrix (ECM) [1]. Nowadays, at least 20 enzymes that share considerable homology within their major domains (signal peptide, propeptide, catalytic, hinge and hemopexin-like domains) were included in MMPs family [2]. Most of MMPs are synthesised and secreted as partially activated latent forms, requiring, for full activation, removal of the entire propeptide domain by proteinases including other MMPs AbstractThe goal of our study was to analyse the prognostic values for some matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in breast cancer. We evaluated the activity and the expression levels of MMP-9, MMP-2, TIMP-1 and TIMP-2 in malignant versus benign fresh breast tumor extracts. For this purpose, gelatinzymography, immunoblotting and ELISA were used to analyse the activity and expression of MMPs and TIMPs. We found that MMP-9 expression level and activity are increased in malignant tumors. In addition, MMP-9/TIMP-1 and MMP-2/TIMP-2 ratio values obtained by us were significantly different in malignant tumors compared to benign tumors. We suggest that the abnormal MMP-9/TIMP-1 balance plays a role in the configuration of breast invasive carcinoma of no special type and also in tumor growth, while altered MMP-2/TIMP-2 ratio value could be associated with lymph node invasion and used as a prognostic marker in correlation with Nottingham Prognostic Index. Finally, we showed that in malignant tumors high expression of estrogen receptors is associated with enhanced activity of MMP-2 and increased bcl-2 levels, while high expression of progesterone receptors is correlated with low TIMP-1 protein levels.

Physical exercise modulates the level of serum MMP-2 and MMP-9 in patients with breast cancer

“…Kadoglou et al (24) demonstrated that exercise reduces MMP-9 serum levels, but not MMP-2 levels, in patients with type 2 diabetes. Additional studies have investigated the function of circulating MMP-2 and MMP-9 in BC patients (51,52); the results revealed increased MMP-9 expression and activity in malignant tumors, and enhanced MMP-2 activity in malignant tumors exhibiting high estrogen receptor expression. These studies indicate that serum levels of MMP-2 or -9 may present useful markers for the staging and prognosis of BC and other types of cancer (53), such as prostate adenocarcinoma, in association with prostate-specific antigen levels, gastric cancer and lung carcinoma (54)(55)(56).…”

Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis

“…The stromal desmoplastic response is characterized by the activation of fibroblasts, increased deposition, cross-linking and remodeling of the ECM, angiogenesis, and invasion of leukocytes. Up-regulated ECM gene expression and elevated MMP activities are not only found in tumors but can also correlate with poor patient prognosis (Jinga et al, 2006). For example, expression levels of the ECM protein lysyl oxidase (LOX), which is responsible for collagen cross-linking, is elevated in cancer patients and associated with metastasis and reduced patient survival (Erler et al, 2006).…”

“…For example, expression levels of the ECM protein lysyl oxidase (LOX), which is responsible for collagen cross-linking, is elevated in cancer patients and associated with metastasis and reduced patient survival (Erler et al, 2006). Furthermore, the increased ratios of MMP2:TIMP2 and MMP9:TIMP1 found in malignant breast tissues have been suggested to play a role in the aggressiveness of invasive breast carcinomas (Jinga et al, 2006).…”

Worse prognosis in breast cancer patients can be predicted by immunohistochemical analysis of positive MMP-2 and negative estrogen and progesterone receptors

“…MMP-2 is a protein associated with metastasis and is extensively studied in several cancers. [11][12][13][14][15][16] ER and MMP-2 have shown a molecular relationship with E2 or estradiol binding in the E domains of ER, present in the plasma membrane. This interaction could activate MMP-2 and MMP-9 with subsequent transactivation of EGFR.…”

“…A loss of control of MMPs can result in pathological processes including inflammation, angiogenesis, cellular proliferation 11,12 and are directly involved in the metastatic tumor cell invasion process. 9 Among them, gelatinase A (MMP-2) is associated with a malignant phenotype, as it is responsible for the degradation of collagen fibers around tumors, thereby releasing these cells from the microenvironment in which they are established.…”