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

¹ Department of Pathology and Forensic Medicine, University of Kuopio, Kuopio, Finland; Departments of ² Pathology, ³ Oncology, ⁴ Otorhinolaryngology, Oral and Maxillofacial Unit, and ⁵ Surgery, Kuopio University Hospital, Kuopio, Finland; and ⁶ Department of Pathology, Centre for Laboratory Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland

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 metastasis-promoting 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 (T₁, 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 (T₁; 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.

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