Immunohistochemical study of matrix metalloproteinase 9 and tissue inhibitor of matrix metalloproteinase 1 in benign and malignant breast tissue--strong expression in intraductal carcinomas of the breast.

OBJECTIVE: Matrix metalloproteinases (MMPs) are involved in carcinogenesis due to their tissue remodeling capability, and there is convincing evidence linking gelatinase B (MMP-9) with malignant cell invasion. Tissue inhibitor 1 of MMP (TIMP-1) is a strong inhibitor of MMP-9 but has also tumor-enhancing effects. Only few data exist on MMP-9 or TIMP-1 expression in tissue samples of different breast histology. METHODS: MMP-9 and TIMP-1 immunoreactivity was examined in a wide range of breast tissue samples differing in histology from usual ductal hyperplasia (UDH) to fully developed ductal breast carcinoma. Immunohistochemical expression of MMP-9 was studied in 178 samples: 31 UDH samples, 29 atypical ductal hyperplasia (ADH) samples, 28 ductal carcinoma in situ (DCIS) samples and 90 ductal invasive carcinoma samples (30 samples of malignancy grades I, II and III, respectively). TIMP-1 expression was also analyzed in 178 breast tissue samples: 41 UDH, 21 ADH and 34 DCIS lesions, and 82 invasive ductal breast carcinomas (25 in grade I, 30 in grade II and 27 in grade III). RESULTS: A significantly distinctive pattern of MMP-9 protein expression was shown in DCIS samples, where 85.7% of the cases showed moderate or strong positivity and negative staining was rare (p = 0.021). Negative or weakly positive MMP-9 staining was the most prominent finding in UDH (71%), ADH (69%) as well as in invasive carcinoma samples (64.4%). Various degrees of TIMP-1 expression were seen in 86.5% of all cases. DCIS and invasive carcinoma samples revealed similar immunostaining: at least some positivity was seen in 91.1% of the DCIS samples and 91.5% of infiltrative carcinomas. Thus, TIMP-1 negativity (22.2%) was significantly associated with hyperplastic lesions (p = 0.026). CONCLUSIONS: These results suggest that MMP-9 and TIMP-1 overexpression are early markers of breast carcinogenesis preceding tumor invasion. Apparently, DCIS carries the risk to evolve into a malignant phenotype according to these markers. The clinical importance of these findings is discussed.

A mutant TP53 gene status is associated with a poor prognosis and anthracycline-resistance in breast cancer patients.

This study evaluates the prognostic and predictive relevance of a mutated p53 in a series of 254 samples from primary breast cancer patients. C-erbB-2 analysis was defined in a limited subpopulation of 79 patients. p53 and c-erbB-2 status was analysed by immunohistochemical staining of the tumour samples. Positive p53 immunostaining was present in 86 cases (34%) and correlated with a high malignant grade, negative progesterone receptor status and ductal histology of tumour. C-erbB-2 positivity was seen in 38 samples (48%). Within an average follow-up time of 74 months, 121 patients developed recurrent or metastatic disease. Patients with mutated p53 showed a statistically significant shorter overall survival and disease-free survival in both univariate and multivariate analyses. The worst clinical outcome was seen in patients who were both p53- and c-erbB-2-positive. The response rate to anthracycline-based chemotherapy in metastatic disease was low in the p53-positive cases. Our results help to clarify the independent prognostic role of a mutated p53 status in breast cancer patients, indicating that this gene might be predictive of anthracycline resistance. Patients with a mutant p53 status and overexpressing c-erbB-2 should be regarded as high-risk cases.