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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

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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 Vol. 10, 7621–7628, November 15, 2004 Clinical Cancer Research 7621 Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Breast Cancer with a Special Reference to Activator Protein-2, HER2, and Prognosis Johanna M. Pellikainen,1,2,3 Kirsi M. Ropponen,2 positive disease. In the univariate survival analysis, positive Vesa V. Kataja,3 Jari K. Kellokoski,4 stromal MMP-9 predicted shorter recurrence-free survival and breast cancer-related survival (0.0389 ؍ RFS; P) 1,2,3,6 5 ؉ ؍ Matti J. Eskelinen, and Veli-Matti Kosma 1 (BCRS; P 0.0081) in ER disease, especially in the sub- ؍ > Department of Pathology and Forensic Medicine, University of ؉ 2 3 group of ER tumors of 2 cm in diameter (T1; P 0.0031 ؍ ,Kuopio, Kuopio, Finland; Departments of Pathology, Oncology 4Otorhinolaryngology, Oral and Maxillofacial Unit, and 5Surgery, for RFS, and P 0.0089 for BCRS). High MMP-9 expres- in the (0.0351 ؍ Kuopio University Hospital, Kuopio, Finland; and 6Department of sion in cancer cells predicted longer RFS (P Pathology, Centre for Laboratory Medicine, University of Tampere whole patient group. In the multivariate analysis of the and Tampere University Hospital, Tampere, Finland whole patient group, the independent predictors of shorter RFS were reduced MMP-9 expression in carcinoma cells ؍ ؍ ABSTRACT (P 0.0248), HER2 overexpression (P 0.0001), and ad- -Shorter BCRS was pre .(0.0002 ؍ vanced-stage disease (P Purpose: In the present study, we investigated the ex- dicted by advanced-stage disease (P < 0.0001). pression and prognostic value of matrix metalloproteinase Conclusions: Expression of MMP-2 and MMP-9 in (MMP)-2 and MMP-9 in breast cancer as well as their breast cancer seems to be partly related to expression of relation to transcription factor activator protein (AP)-2 AP-2 and HER2. Positive stromal MMP-9 expression pre- and HER2 oncogene. The role of invasion and metastasis- dicts poor survival in the hormone-responsive small tumors, promoting MMPs and their potential regulators, AP-2 and whereas MMP-9 expression in carcinoma cells favors sur- HER2, is currently still unclear in breast cancer. vival. Evaluation of MMP-9 expression seems to add valua- Experimental Design: MMP-2 and MMP-9 expressions ble information on breast cancer prognosis. were analyzed immunohistochemically in a large prospec- tive series of 421 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hos- INTRODUCTION pital (Kuopio, Finland). The relation of MMP-2 and MMP-9 Matrix metalloproteinase (MMP)-2 and MMP-9 (gelatin- expressions to AP-2, HER2, clinicopathological data, and ase A and B) are zinc-dependent endopeptidases of a large survival was investigated. MMP family (1, 2). MMP-2 and MMP-9 are related to tumor Results: Both MMP-2 and MMP-9 were expressed in invasion and metastasis by their capacity for tissue remodeling the cytoplasm of malignant and stromal cells. High expres- via extracellular matrix as well as basement membrane degra- sion of MMPs in carcinoma cells was related to small tumors dation and induction of angiogenesis (1, 2). These gelatinases are secreted as zymogens and cleaved to the active form, and (T1, stage I), whereas positive stromal expression of MMPs was associated with aggressive factors. High expression of their function is tightly regulated by several different mecha- MMP-2 and MMP-9 in carcinoma cells, but not in stromal nisms (1, 2). In breast cancer, both gelatinases seem to be cells, was related to high AP-2 expression. Positive stromal expressed in cancer tissue, although the results have not been MMP-2 expression was associated with HER2 overexpres- consistent (3–6). To date, only a few studies have investigated sion in the whole patient group and in the node-negative the prognostic value of MMP-2 and MMP-9 in breast cancer patient subgroup. Positive stromal MMP-9 expression was (5, 7–10). related to HER2 overexpression in estrogen receptor (ER)- Aberrant expressions of transcription factor activator pro- tein (AP)-2 and HER2 oncogene are related to disease progres- sion and increased invasive capacity in breast cancer (11–13), which may be due in part to increased MMP activity (14, 15). Received 5/31/04; revised 8/8/04; accepted 8/13/04. Indeed, AP-2 has been shown to be critically responsible for Grant support: EVO funding of Kuopio and Tampere University MMP-2 transcription (16–22) and to enhance MMP-9 promoter Hospitals, Kuopio University Funding, Research Foundation of Orion activity (23, 24). In melanoma cells, inactivation of AP-2 leads Corporation, The Culture Fund of Finland (North Savo Fund), and The to increased invasiveness via increased MMP-2 expression and Finnish Medical Society Duodecim. activity (14), whereas in breast cancer, the relationship between The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked AP-2 and gelatinase expression has not been studied. The effect advertisement in accordance with 18 U.S.C. Section 1734 solely to of HER2 overexpression on the invasion capacity of tumor cells indicate this fact. is related, at least in part, to the up-regulation of MMP-2 and Requests for reprints: Veli-Matti Kosma, Department of Pathology MMP-9 expression and proteolytic activity (15, 25–28). Fur- and Forensic Medicine, University of Kuopio, P. O. Box 1627, FIN- 70211 Kuopio, Finland. Phone: 358-17-162-750, Fax: 358-17-162-753; thermore, c-ErbB ligands are able to up-regulate several MMPs E-mail: [email protected]. (29, 30). To the best of our knowledge, this is the first study to ©2004 American Association for Cancer Research. investigate the relation of MMP-2 and MMP-9 to AP-2 and Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2004 American Association for Cancer Research. 7622 Gelatinases, AP-2, HER2, and Prognosis in Breast Cancer HER2 expression in a large prospective clinical breast cancer Table 1 Clinicopathological data study. Characteristic n (%) No. of patients 421 (100) Age (y) PATIENTS AND METHODS Mean (range) 59.2 (23.3–91.6) Patients. The present study is part of the Kuopio Breast Tumor size Cancer Project, a prospective long-term clinical study involving T1 221 (53) T 166 (39) 520 breast cancer patients (31–34) diagnosed among the 2,500 2 T 24 (6) women who were referred to Kuopio University Hospital be- 3 T4 10 (2) cause of a clinical breast lump, suspicious mammographic find- Lymph node status ing, or a breast symptom (e.g., pain, nipple discharge) between Negative 245 (58) April 1990 and December 1995. Women willing to participate in Positive 168 (40) Unknown 8 (2) the project were interviewed and examined by a trained study Stage nurse before any diagnostic procedures. The participation rate of I 162 (39) patients with diagnosed breast cancer was 98%. Thus, the pa- II 212 (50) tient series represents unselected typical breast cancer cases III 39 (9) from the University Hospital catchment area. Altogether, 479 Unknown 8 (2) Histological type invasive and 41 noninvasive carcinomas were diagnosed. After Ductal 272 (64) surgical treatment, the patients were offered adjuvant chemo- Lobular 67 (16) therapy and/or hormonal therapy and radiotherapy, depending Other 82 (20) on the mode of the surgery, the patient’s menopausal status, and Histological grade I 110 (26) the stage of the disease, according to the national guidelines II 192 (46) (35). In brief, postoperative radiotherapy was given to all pa- III 119 (28) tients treated with breast-conserving surgery and to all patients ER status with axillary node-positive (pNϩ) status irrespective of the Positive 326 (78) mode of surgery. All premenopausal patients with pNϩ status Negative 94 (22) Data not available 1 (Ͻ1) and some with axillary node-negative (pNϪ) status presenting PR status with other adverse prognostic factors, such as estrogen receptor Positive 261 (62) (ER)/progesterone receptor (PR) negative or poorly differenti- Negative 158 (38) Ͻ ated tumor, were given adjuvant chemotherapy (intravenous Data not available 2 ( 1) Menopausal status cyclophosphamide, mitoxantrone, methotrexate, and 5-fluorou- Premenopausal 132 (31) racil) for six cycles, which was the standard therapy at the time. Postmenopausal 289 (69) All postmenopausal women with ER- and/or PR-positive tumors Recurrence at 5 y were adjuvantly treated with either tamoxifen or toremifene for No 346 (82) 3 years within a clinical study protocol. Thus, within a stage, the Yes 75 (18) Cause of death at 5 y postoperative treatment was rather uniform, with only a few Alive 335 (79) exceptions due to concurrent conditions. Stage was assessed by Breast cancer 49 (12) using the UICC classification (36). Patients with noninvasive Other 37 (9) carcinomas, a previous history of breast cancer, metastatic dis- ease (stage IV), or insufficient tumor material were excluded from the present study. Thus, 421 patients with sufficient pri- mary tumors and complete clinical histories were available for four original sections of the primary tumor. All tumors were MMP-2 analyses, 415 patients were available for MMP-9 anal- simultaneously reevaluated for histologic type and grade by two yses, 417 patients were available for AP-2 analyses, and 419 senior pathologists, who were unaware of the clinical data. The patients were available for HER2 analyses. The mean age of the most representative blocks were selected for cutting into new 421 patients was 59.2 years (median, 56.8 years; range, 23.3– 5-␮m–thick sections for immunohistochemical analyses. 91.6 years). The mean follow-up time was 55.0 months (median, Immunohistochemistry. The MMP-2 and MMP-9 stain- 57.5 months; range, 1.2–115.1 months). During the first 5 years ings were demonstrated using Sequenza Immunostaining Center of follow-up, 75 of the 421 patients (18%) had a recurrence, 49 (Shandon Scientific Limited, Astmoor, United Kingdom).
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