Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Breast Cancer with a Special Reference to Activator Protein-2, HER2, and Prognosis

Abstract

Purpose: In the present study, we investigated the expression and prognostic value of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer as well as their relation to transcription factor activator protein (AP)-2 and HER2 oncogene. The role of invasion and metastasispromoting MMPs and their potential regulators, AP-2 and HER2, is currently still unclear in breast cancer.Experimental Design: MMP-2 and MMP-9 expressions were analyzed immunohistochemically in a large prospective series of 421 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hospital (Kuopio, Finland). The relation of MMP-2 and MMP-9 expressions to AP-2, HER2, clinicopathological data, and survival was investigated.Results: Both MMP-2 and MMP-9 were expressed in the cytoplasm of malignant and stromal cells. High expression of MMPs in carcinoma cells was related to small tumors (T 1 , stage I), whereas positive stromal expression of MMPs was associated with aggressive factors. High expression of MMP-2 and MMP-9 in carcinoma cells, but not in stromal cells, was related to high AP-2 expression. Positive stromal MMP-2 expression was associated with HER2 overexpression in the whole patient group and in the node-negative patient subgroup. Positive stromal MMP-9 expression was related to HER2 overexpression in estrogen receptor (ER)-positive disease. In the univariate survival analysis, positive stromal MMP-9 predicted shorter recurrence-free survival (RFS; P ‫؍‬ 0.0389) and breast cancer-related survival (BCRS; P ‫؍‬ 0.0081) in ER؉ disease, especially in the subgroup of ER؉ tumors of <2 cm in diameter (T 1 ; P ‫؍‬ 0.0031 for RFS, and P ‫؍‬ 0.0089 for BCRS). High MMP-9 expression in cancer cells predicted longer RFS (P ‫؍‬ 0.0351) in the whole patient group. In the multivariate analysis of the whole patient group, the independent predictors of shorter RFS were reduced MMP-9 expression in carcinoma cells (P ‫؍‬ 0.0248), HER2 overexpression (P ‫؍‬ 0.0001), and advanced-stage disease (P ‫؍‬ 0.0002). Shorter BCRS was predicted by advanced-stage disease (P < 0.0001).Conclusions: Expression of MMP-2 and MMP-9 in breast cancer seems to be partly related to expression of AP-2 and HER2. Positive stromal MMP-9 expression predicts poor survival in the hormone-responsive small tumors, whereas MMP-9 expression in carcinoma cells favors survival. Evaluation of MMP-9 expression seems to add valuable information on breast cancer prognosis.

Study of matrix metalloproteinases and their inhibitors in breast cancer

“…Our results are in accordance with those of previous reports showing that a high MMP-9 expression correlates significantly with tumoral aggressiveness and poor prognosis (Chantrain et al, 2004;Li et al, 2004;Pellikainen et al, 2004), as well as with other studies where high MMP-2 expression in carcinoma cells, in contrast, has been related to only a few inverse prognostic factors (Talvensaari-Mattila et al, 1998;Nakopoulou et al, 2003) or shown to have no association with clinicopathological parameters in breast cancer (Jones et al, 1999;Hirvonen et al, 2003;Talvensaari-Mattila et al, 2003). It has also been described that as breast cancer progresses, MMP-2 production increases during the early phases, whereas activation of MMP-9 occurs during the late cancerous stage (Liotta and Kohn, 2001), which could explain their different impact on prognosis in clinically detected invasive breast tumours.…”

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling

“…Upregulation of this gene may be linked to increased levels of HMGA1 and TFAP2A, which are both positive regulators of MMP9 (Liu et al, 1999;Sivak et al, 2004). In breast cancer patients, TFAP2A is highly associated with MMP9 expression (Pellikainen et al, 2004). NRC3C1 is a nuclear receptor that can inhibit expression of MMP9 (Cha et al, 1988).…”

Prognostic Value of Matrix Metalloproteinase 9 Expression in Breast Cancer Patients: A Meta-analysis

“…MMP-9 mRNA expression was evaluated in another study (Sieuwerts et al, 2005). Furthermore, two studies (Pellikainen 2004;Gonzalez et al, 2010) provided information about MMP-9 expression in tumor cells and stromal tissues respectively without general result, which we treated independently. Eventually, 15 studies met the inclusion criteria were included (Scorilas et al, 2001;Fan et al, 2003;Li et al, 2004;Pellikainen et al, 2004;Rahko et al, 2004;Li et al, 2006;Mylona et al, 2007;Vizoso et al, 2007;Feng et al, 2008;Wu et al, 2008;Zhao et al, 2008;Tian et al, 2009;Gonzalez et al, 2010;Sullu et al, 2011;Oscar et al, 2012).…”