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.

Activator protein‐2 (AP‐2) transcription factors are involved in the regulation of cell proliferation, differentiation, apoptosis and carcinogenesis. AP‐2α has been suggested to function as a tumor suppressor in many cancers and AP‐2γ to be a marker of testicular and germ cell malignancies. At least 3 of the 5 AP‐2 family members identified to date, AP‐2α, AP‐2β and AP‐2γ, are known to be expressed in breast tissue and thought to coordinate the growth and development of the breast via regulation of several breast‐related genes such as human epidermal growth factor receptor‐2 (HER2) and estrogen receptor (ER). The function of AP‐2α seems to be tumor suppressive in breast tissue, whereas the role of the other AP‐2 family members is less well known. In this review, we summarize the current knowledge of AP‐2 in carcinogenesis, especially in breast cancer. © 2007 Wiley‐Liss, Inc.

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