Gelatinase A, membrane type 1 matrix metalloproteinase, and extracellular matrix metalloproteinase inducer mRNA expression: Correlation with invasivegrowth of breast cancer

Invasive breast cancer varies widely in biologic aggressiveness, from fairl y indolent tumors to rapidly disseminating carcinomas. Matrix metalloprotei nases have enzymatic activity and assist in tumor invasion by degrading bas ement membranes and extracellular matrix. The extracellular matrix metallop roteinase inducer EMMPRIN is thought to stimulate fibroblasts to produce th e zymogen pro-gelatinase A. The membrane type 1-matrix metalloproteinase (M T1-MMP) is thought to assist in tumor invasion and metastasis by activating pro-gelatinase A, which shows enhanced expression in various tumors. Overe xpression of gelatinase A has shown to correlate with a malignant phenotype in many tumor forms. The aim of the study was to investigate the mRNA expr ession pattern of MT1-MMP, gelatinase A, and EMMPRIN in breast tumors. Form alin-fixed paraffin-embedded breast tissue samples from 18 patients operate d on,vith breast-conserving surgery for invasive breast carcinoma <20 mm be tween 1977 and 1985 were analyzed using the mRNA in situ hybridization tech nique. Most of the patients were node-negative (15/18) and underwent postop erative irradiation to the breast (16/18), The median age at diagnosis was 52 years (21-83 gears). At the time of the study 11 patients were alive, 4 without recurrence; 7 patients had been operated for ipsilateral breast tum or recurrences, and 2 had distant metastases. The median follow-up was 112 months (102-193 months). Se, en patients died of disseminated breast cancer ; their median follow-up was 43 months (22-116 months). S-35-labeled antise nse and sense mRNA probes transcribed from linearized plasmids containing c DNA for the matrix metalloproteinases gelatinase A and MT1-MMP and the glyc oprotein EMMPRIN were hybridized to 5 mu m paraffin-embedded tissue section s, Several invasive carcinomas were surrounded by normal tissue and carcino ma in situ lesions. Gelatinase A, MT1-MMP, and EMMPRIN mRNA expression were detected in all of the carcinomas. The gelatinase A mRNA expression was ma inly localized to stromal cells at moderate to high levels surrounding the invading carcinoma cells but was also seen in single cells at low levels in in situ lesions and in some normal glandular cells. MT1-MMP and EMMPRIN we re expressed in all of the carcinomas and were mainly localized to tumor ce lls; but they were also seen to some extent in single cells at low levels i n in situ lesions and in normal glandular cells. No differences in levels o f expression for gelatinase A, MT1-MMP, or EMMPRIN were seen in patients wh o survived compared to patients who died from metastatic disease, The co-ex pression of gelatinase A, MT1-MMP, and EMMPRIN mRNA in invasive breast carc inoma supports the theory that these proteins interact and are important fo r the invasive phenotype in breast carcinoma, Hence EMMPRIN may be a centra l factor for stimulation of gelatinase A activation, Specific inhibitors fo r individual MMP members could in the future be target-specific events in b reast tumor progression. Inhibition of EMMPRIN could be such a target.