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Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 Mrnas in Ductal Carcinoma in Situ and Invasive Ductal Carcinoma of the Breast

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Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 Mrnas in Ductal Carcinoma in Situ and Invasive Ductal Carcinoma of the Breast Yonsei Medical Journal Vol. 47, No. 3, pp. 333 - 342, 2006 Expression of MT-1 MMP, MMP2, MMP9 and TIMP2 mRNAs in Ductal Carcinoma in Situ and Invasive Ductal Carcinoma of the Breast Hee Jung Kim,1 Chan-il Park,2 Byeong Woo Park,3 Hy-de Lee,3 and Woo Hee Jung2 1Department of Pathology, MizMedi Breast Center, MizMedi Hospital, Seoul, Korea; 2Department of Pathology, 3Surgery, Yonsei University College of Medicine, Seoul, Korea. We investigated the expression of membrane type-1 (MT1)- in tumor growth, as well as the utility of CD44std as a pro- MMP, MMP2, MMP9 and TIMP2 mRNAs and their roles in gnostic indicator of breast cancer. ductal carcinoma in situ (DCIS) and T1 and T2 invasive ductal Key Words: Carcinoma, ductal, breast, MT1-MMP, MMP2, carcinoma of the breast. We further compared these two types MMP9, TIMP2, prognosis of carcinomas for differences in microvessel density, and expres- sion of angiogenic factors and CD44std. MT1-MMP, MMP2, MMP9 and TIMP2 mRNA were expressed in both DCIS and invasive ductal carcinomas. Expression rates of MT1-MMP, INTRODUCTION MMP2, MMP9 and TIMP2 mRNAs were not statistically dif- ferent between DCIS and invasive ductal carcinomas, nor did Degradation of basement membranes and ex- they differ statistically when grouped by tumor size, histologic grade or nuclear grade of invasive ductal carcinoma. Microvessel tracellular matrix is an essential process in inva- density and expression of VEGF and TGF-β1 were not statisti- sion and metastasis in malignant tumors. MMP, cally different between DCIS and invasive ductal carcinoma. potent proteolytic enzymes are known to play key CD44std expression was significantly increased in DCIS roles in this process. Within the MMP families, compared to invasive ductal carcinoma (p < 0.05) and it was MMP-2 (gelatinase A, 72 kDa) and MMP-9 (gela- also significantly increased in lower clinical stage, histologic tinase B, 92 kDa) cleave the type IV collagen and grade and nuclear grade of invasive ductal carcinoma (p < 0.05). Axillary node metastasis was significantly correlated with gelatin, which are the principal structural compo- 1 MT1-MMP mRNA, VEGF and TGF-β1 expression (p < 0.05) nents of basement membrane. Expression of and MT1-MMP mRNA was positively correlated with VEGF MMP2 and MMP9 has been reported in breast expression and TIMP2 mRNA (p < 0.05). In summary, patterns cancer,2-4 colon cancer,5 skin tumors6 and lung can- of MMP mRNA expression in DCIS and invasive ductal cer7 and their expression has been correlated with carcinoma suggest that the invasive potential of breast carcinoma local invasion by the tumor, lymph node metastasis is already achieved before morphologically overt invasive 2,3 growth is observed. As MT1-MMP mRNA expression is and survival rates. Membrane type-1 (MT1) MMP significantly correlated with axillary nodal metastasis, it may be specifically activates the pro-gelatinase, MMP2 on useful as a prognostic indicator of invasive ductal carcinoma. the tumor cell surface in vitro and binds with Considering the positive correlation of MT1-MMP mRNA and TIMPs, hence, may have a role in controlling TIMP2mRNA expression, our finding supports a role for TIMP2 MMP2 activity.8 The cell surface adhesion mole- cule, CD44, is also an important factor in invasion 9-11 Received June 15, 2005 and metastasis. A recent report showed that Accepted November 18, 2005 CD44 can localize active MMP9 protein to the This study was supported in part by the Yonsei University Re- tumor cell surface where the CD44-MMP9 com- search Fund of 2001 and by the BMS Korea Research Fund of 2001. plex induces TGF-β1 activation, which in turn Reprint address: requests to Dr. Woo Hee Jung, Department of promotes tumor invasion and angiogenesis.12 Pathology, Yonsei University College of Medicine, Yongdong Severance Hospital, 146-92 Dogok-dong, Kangnam-gu, Seoul To further understand their roles in breast can- 135-720, Korea. Tel: 82-2-2019-3540, 3541, Fax: 82-2-3463-2103, cer, we investigated the expression of MT1-MMP, E-mail: [email protected] MMP2, MMP9 and TIMP2 mRNAs using mRNA in Yonsei Med J Vol. 47, No. 3, 2006 Hee Jung Kim, et al. situ hybridization and microvessel density counts. employed were as follows: anti-CD44std (H-CAM, The expression of angiogenic factors and CD44std mouse monoclonal antibody, Novocastra, New- as measured by immunohistochemical staining was castle, UK, 1:50), anti-Factor VIII (clone F8/86, compared in ductal carcinoma in situ (DCIS) and mouse monoclonal antibody, DAKO, CA, USA, T1 and T2 invasive ductal carcinoma of the breast. 1:50), anti-TGF-β1 (TB21, mouse antihuman anti- Further, we explored the roles of MT1-MMP, body, Serotec, Oxford, UK, 1:100), and anti-VEGF MMP2, MMP9 and TIMP2 and the relationship (sc-152, rabbit polyclonal antibody, Santa Cruz, between MMP and TMP mRNA, CD44std, micro- CA, USA, 1:250). After incubation with the pri- vessel density and angiogenic factors. mary antibody, the slides were treated with, bio- tinylated anti-mouse, rabbit IgG (DAKO) and a complex of peroxidase conjugated streptavidin MATERIALS AND METHODS (DAKO) in the order listed. The final reaction products were visualized with 3-amino-9-ethyl- Selection of patients and tumors studied carbazole and light hematoxylin counterstain. Primary breast cancer tissue obtained from 84 Interpretation of immunohistochemical staining mastectomy patients was examined. The samples included 21 cases of DCIS and 63 cases of T1 or Immunohistochemical staining for CD44std was T2 invasive ductal carcinoma with the tumor size interpreted as positive when more than 10% of of less than 5 cm. Patients with multiple foci of tumor cells were stained along the cytoplasmic disseminated tumor and a history of previous membrane. A slide was scored as positive for axillary surgery on the same side of the body TGF-β1 and VEGF when more than 5% of tumor were excluded. cells were stained in the cytoplasm of tumor cells. Clinicopathological findings Measurement of microvessel density The patients'age, tumor size, lymph node sta- One representative tumor block was stained with tus, clinical stage and histologic findings were anti-Factor VIII antibody. Singular or clusters of reviewed. Nuclear grades of DCIS and invasive endothelial cells irrespective of whether they for- ductal carcinoma were grouped according to med a lumen were counted as individual microves- Black's criteria.13 Histologic grading of invasive sels and blood vessels with thick muscular walls ductal carcinoma was classified according to the were excluded. Microvessels were counted in the modified Bloom and Richardson method.14 highly vascular field of the tumor- stroma interface or the central area of the tumor at × 200 mag- Immunohistochemical staining nification and the average number of microvessels obtained in three different fields was calculated. Immunohistochemical staining was performed by the labeled streptavidin-biotin method using a In situ hybridization LSAB kit (DAKO, Carpinteria, CA, USA). One representative section of the tissue was cut at 4 μm In situ hybridization was done with the Inno and placed on poly-L-lysine coated slides. The GenexTM universal ISH detection kit (InnoGenex, slides were deparaffinized, rehydrated, immersed San Ramon, CA, USA). The following probes were in 10 mM sodium citrate (pH 6.0), and pretreated labelled with FITC: MT1-MMP, MMP9, TIMP2 in a microwave oven for 10 minutes, followed by (human, Biognostik, Germany) DNAs and and a rinsing with TBS buffer (pH 7.6) for 10 minutes. MMP2 oligonucleotide (5'-TGG/GCT/ACG/GCG/ After blocking with 3% hydrogen peroxide and CGG/CGG/CGT/GGC-3'FITC, Genemed Syn- normal goat serum, respectively, for 30 minutes thesis, Inc., South San Francisco, CA, USA.) Depa- each, the slides were incubated at 4 overnight raffinized sections were blocked by washing in with primary antibodies. The primary antibodies sterile deionized water containing 0.2% RNase for Yonsei Med J Vol. 47, No. 3, 2006 Brief running Title: Expression of MMP and TIMP mRNAs in the Breast Carcinoma 5 minutes and pretreated with proteinase K at 3 SPSS version 9.0 software program and a statis- 7 for 15 minutes. Slides were heated in a micro- tical difference was considered significant when wave for 2 minutes, cooled at room temperature the p value was 0.05 or less. for 10 minutes, postfixed with 1% formalin/ RNase-free PBS for 10 minutes, and washed twice with sterile deionized water containing 0.2% RESULTS RNase. Probes (MMP2 1:20, MMP9 1:15, TIMP2 1:15, MT1-MMP 1:15) were diluted into the manu- Expression of MMP and TIMP mRNA in DCIS facturer's hybridization solution and applied to the and invasive ductal carcinoma of the breast slides. A coverglass was applied and slides were heated to 80 for 5 minutes before hybridizing at MT1-MMP, MMP2, MMP9 and TIMP2 mRNAs 37 for 16 hours. Posthybridization washing was were expressed in 60%, 65%, 50%, and 35% of done in 1 × and 0.1 × SSC solution containing DCIS and 46%, 58%, 44% and 38% of invasive power block reagent for 5 minutes at room tem- ductal carcinoma, respectively (Table 1). There perature followed by biotinylated anti-probe was no statistical difference in MMP and TIMP antibodies for 20 minutes at room temperature. mRNA expression levels between DCIS and After washing with 1 × PBS, slides were treated invasive ductal carcinoma. MMP mRNA expres- with streptavidin horseradish peroxidase conjugate sion using in situ hybridization was more intense for 20 minutes, stained with aminoethyl carbazole at the peripheral rim of tumor nests of the in- (AEC), and examined by light microscopy. vasive ductal carcinoma. Tumor cells were stained Positive controls were made with fluorescei- in both nuclei and cytoplasm with the nuclei ex- nated poly (A) oligonucleotides and the negative hibiting a stronger signal.
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