SciMedWeb® - MATRIX METALLOPROTEINASE-11 (MMP11)

Cell lines:
- MCF-7 and MDA-MB-231, but not ZR-75, TT-47D, BT20 and BT-474 breast cancer cell (BCC) lines were found to directly activate the MMP11 promoter transiently transfected in NIH3T3 fibroblasts. The putative response element in the MMP11 promoter, which lies between 0.46 and 3.4 kb upstream of the transcription start site, was able to effect a 2- to 3-fold increase in downstream gene expression (Ahmad A. et al., 1997).

Tumors:
- MMP11 expression was studied during brreast cancer progression. MMP11 was expressed in all invasive breast carcinomas, in a number of their metastases, and in some in situ carcinomas where the probability of detecting MMP11 transcripts correlated with the known risk of these carcinomas to become invasive. MMP11 RNA and protein were specifically detected in fibroblastic cells immediately surrounding the neoplastic cells in both primary and metastatic tumors. Interestingly, urokinase (gene PLAU) and MMP11 exhibited very similar patterns of expression in breast carcinomas, suggesting that their products may cooperate during cancer progression (Wolf C. et al., 1993).

- MMP11 expression was studied by Northeern blotting in 222 tissue samples including primary and metastatic breast carcinoma and normal breast tissue. About 62% of primary and metastatic breast carcinomas, but only 1 of 10 in situ ductal carcinomas, expressed MMP11. MMP11 mRNA was found more often in estrogen-receptor-positive carcinomas and in histological grade-1 carcinomas. There was no significant correlation between MMP11 expression and other prognostic factors, including tumor size, lymph-node involvement, age of patient, vascular invasion and cathepsin-D (Hähnel E. et al., 1993).

- MMP11 mRNA was isolated from over 200 surgical specimens and studied by Northern blots. 60% of primary and metastatic breast carcinomas contained MMP11-mRNA. The expression of ST3 was mainly confined to invasive carcinomas and was observed less frequently in pure ductal carcinoma in situ (DCIS) lesions (Hähnel E. et al., 1994).

- The MMP11 gene was shown to be overexppressed in most types of human carcinomas, including breast carcinoma where MMP11 RNA was detected in 95% (99 of 104) of invasive primary tumors. Both MMP11 protein and RNA were detected in fibroblastic cells immediately surrounding the cancer cells, but not in the malignant cells or in stromal cells at a distance from them. The MMP11 gene also was expressed in some in situ breast carcinomas, where MMP11 expression correlated with the known risk of these tumors to become invasive (Basset P. et al., 1994).

- Levels of MMP11 mRNA in breast cancer have been reported to predict a greater likelihood of recurrent disease (Engel G. et al., 1994) and MMP11 protein levels in breast cancer sections have been shown to be associated with poor prognosis (Chenard M.P. et al., 1996).

- The distribution of cathepsin D (CTSD)), stromelysin 3 (MMP11), and urokinase plasminogen activator (PLAU) gene expression was compared by in situ hybridisation on serial cryo-sections of different benign and malignant tumors. CTSD expression was found to be higher in adenocarcinomas compared to non-tumoral glands. The CTSD RNA was located in mammary epithelial cancer cells rather than in fibroblasts, indicating that the CTSD gene was overexpressed in cancer cells, where the corresponding protein determined by immunohistochemical staining had been shown to be accumulated. In contrast MMP11 mRNA was mostly expressed in peritumoral fibroblasts rather than in cancer cells. PLAU mRNA was detected both in tumor cells and in stromal cells. In benign lesions the 3 protease mRNAs were mostly found in epithelial cells. Stromal cells expressed PLAU mRNA in 5 of 7 lesions, CTSD and MMP11 in only one sample (Escot C. et al., 1996).

- The expression of MMP11 was compared wwith the distribution of tumor microvessels in invasive breast carcinomas. The highest level of MMP11 mRNA in each tumor was recorded and compared to the highest microvessel density. No correlation between these two parameters was observed by analysis of 63 tumors. Detailed examination of 19 individual tumors did not reveal any correlation between the distribution of MMP11 mRNA and microvessels. MMP11 expression was observed to correlate with long-term survival of the patients, whereas microvessel density did not correlate (Linder C. et al., 1997).

- By immunostaining, MMP11 was not obserrved in nonmalignant breast tissue. Invasive ductal carcinomas (IDC) were found to express significantly more MMP11 than invasive lobular carcinomas. While MMP11 was mainly observed in stromal fibroblast-like cells surrounding the breast cancer cells (BCC), certain BCC that have undergone a degree of epithelial-to-mesenchymal transition, in the so-called metaplastic carcinomas, could express MMP11 mRNA and protein. Patients with IDC who had moderate to strong MMP11 levels had significantly shorter disease-free survival than those with negative or weak MMP11 levels. Furthermore, in node-positive IDC patients, multivariate analysis revealed that MMP11 was a strong, independent prognostic parameter for disease-free survival (Ahmad A. et al., 1998).

- The association among matrix metalloprroteinases (gelatinases A/MMP-2 and B/MMP-9, stromelysin-3/MMP-11 and matrilysin/MMP-7) mRNAs expressed in primary breast carcinomas was investigated and standard prognostic parameters and clinical outcome. mRNA levels were determined by Northern analysis in samples of 81 breast cancer patients (median follow-up, 40 months) and 27 samples of uninvolved adjacent breast tissue. Proteases were expressed by the majority of the tumors and normal breast tissues examined. MMP-11, MMP-2 and MMP-7 mRNAs were more often expressed at high levels in carcinomatous than in normal breast tissues. Differences in the distribution of MMP-9 mRNA were not found. However, paired normal tissues generally produced weaker signals when compared to matched tumor samples. Univariate analysis showed no significant association of MMP-2 and MMP-7 mRNAs with the classical prognostic markers (age, menopausal status, stage, size, nodal status, vascular infiltrate, necrosis, steroid receptors, metastasis and survival). Overexpression of MMP-11 was more frequently found in tumors of post-menopausal women (P < 0.022). Elevated expression of MMP-9 mRNA was associated with the presence of vascular infiltrate (P < 0.026), necrosis (P < 0.039), PR negative tumors (P < 0.014) and inversely correlated to the number of survivors (P < 0.021). Multivariate analysis including 68 patients for whom all information was available indicated that neither stromelysin correlated significantly with pathological, clinical or biochemical features. High levels of MMP-2 and -9 mRNAs were inversely associated with the number of survivors (Pacheco M.M. et al., 1998).

- MMP11 was found non-suitable for RT-PCCR detection of submicroscopic lymph node metastases in breast cancer, as its transcript was also detected in the great majority of control (from non-cancer patients) lymph nodes tested (Merrie AEH et al., 1999).

- In 1348 node-positive (NPBC) and node--negative (NNBC) breast cancers diagnosed between 1980 and 1986 and with a minimum follow-up of 5.2 years, cathepsin d (CTSD) expression was assessed by immunohistochemistry on archival material using a polyclonal antibody. Cancer cells expressed CTSD (more than 10% cells expressing CD) in 38.9% of cases and reactive stromal cells in 43.6%. CTSD expression by reactive stromal cells, and not cancer cells, correlated with several factors of poor prognosis by cancer cells. A strong association was also found with expression of other proteases (stromelysin-3/MMP11, gelatinase A/MMP2, and urokinase plasminogen activator/PLAU) by these same reactive stromal cells (Tetu B. et al., 1999).

- cDNA arrays were used to study the quaantitative mRNA expression levels of 176 candidate genes in 34 primary breast carcinomas. To identify genes differentially expressed between breast tumors (T, median expression value in the 34 tumors) and normal breast (NB), the T/NB ration was calculated. Genes for which T/NB was >= 5 included GZMH, STMY3/MMP11, CRABP2, GATA3, CD2, CREBBP, GRB2. Genes whose expression was more than 5-fold lower in tumors included DES, FOS, TFAP4, TNXA, PRL, CSH1, TEK, ATF3, PDNP2, TGFBR3, DTR, HRB, PLA2G2A. When gene expression profiles in estrogen receptor positive (ER+) and ER-negative (ER-) tumors were compared, the ER+/ER- ratio was >= 4 for GATA3 and GZMA, and <= 4 for CD3G and IL2RG. When the group of node-negative tumors (N-) and the group with massive axillary extension (10 or more positive nodes, 10N+) were compared, the ratio N-/10N+ was >= 4 for GATA3, THBS1, EGFR, PDNP2, ATF3, NFIA, SELP, GZMA and CDH1; it was <= 4 for ERBB2 and PPP2R5C (Bertucci F. et al., 2000).

- MMP11 expression is stimulated by trannsforming growth factor-beta in osteoblasts and fibroblasts. This effect could play a role in the metastasis of breast cancer cells and their homing and survival in bone (Delany A.M. and Canalis E., 2001).

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Delany A.M. and Canalis E. (2001) The metastasis-associated metalloproteinase stromelysin-3 is induced by transforming growth factor-beta in osteoblasts and fibroblasts. Endocrinology 142, 1561-1566. (PubMed)
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Escot C. et al. (1996) Cellular localisation by in situ hybridisation of cathepsin D, stromelysin 3, and urokinase plasminogen activator RNAs in breast cancer. Breast Cancer Res. Treat. 38, 217-226. (PubMed)
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Hähnel E. et al. (1994) Expression of stromelysin-3 and nm23 in breast carcinoma and related tissues. Int. J. Cancer 58, 157-160. (PubMed)
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Linder C. et al. (1998) Correlation between basic fibroblast growth factor immunostaining of stromal cells and stromelysin-3 mRNA expression in human breast carcinoma. Br. J. Cancer 77, 941-945. (PubMed)
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Pacheco M.M. et al. (1998) Expression of gelatinases A and B, stromelysin-3 and matrilysin genes in breast carcinomas: clinico-pathological correlations. Clin. Exp. Metastasis 16, 577-585. (PubMed)
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Markers in breast cancer

Matrix metalloproteinase-11
(MMP11, MMP-11)

Other name(s)

Molecular biology

Breast cancer

References

See also

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