Expression of tissue inhibitor of matrix metalloproteinases (TIMP)-3 protein in invasive breast carcinoma: Relation to tumor phenotype and clinical outcome

Introduction Our aim was to study the expression pattern of tissue inhibitor of metalloproteinases ( TIMP)-3 protein in invasive breast carcinoma, and its clinicopathological and prognostic value as well as its relation to markers indicative of the tumor phenotype. Methods Immunohistochemistry was performed on paraffinembedded tissue specimens from 173 invasive breast carcinomas to detect the proteins TIMP-3, estrogen receptor ( ER), progesterone receptor, p53, c- erbB-2, topoisomerase IIa and Bcl-2. Results TIMP-3 protein was immunodetected in the cytoplasm of the malignant cells and the peritumoral stroma, as well as in in situ carcinoma and normal epithelium. Reduced expression of TIMP-3 protein within cancer cells was correlated with carcinomas of high nuclear and histological grade ( p = 0.032 and p = 0.015, respectively), and low ER expression ( p = 0.053). Moreover, TIMP-3 immunopositivity was inversely correlated with the expression of p53 and topoIIa proteins ( p = 0.002 and p = 0.008, respectively), whereas it was positively associated with Bcl- 2 expression ( p = 0.020). Reduced expression of TIMP- 3 protein within cancer cells was found to have an unfavorable impact on disease- free survival ( p = 0.052) in the entirety of the patient population, as well as in both subgroups of lymph- node- positive and mutant- p53- negative patients ( p = 0.007 and p = 0.037, respectively). Stromal localization of TIMP- 3 protein was found to have no clinicopathological or prognostic value. Conclusion This is the first immunohistochemical study to show that TIMP- 3 protein within cancer cells is associated with tumor phenotype. Reduced expression of TIMP- 3 protein within cancer cells was found to correlate with an aggressive tumor phenotype, negatively affecting the disease- free survival of both subgroups of lymph node- positive and mutant- p53- negative patients.