Expression of tissue inhibitor of matrix metalloproteinases (TIMP)-3 protein in invasive breast carcinoma: relation to tumor phenotype and clinical outcome.
BACKGROUND
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 paraffin-embedded tissue specimens from 173 invasive breast carcinomas to detect the proteins TIMP-3, estrogen receptor (ER), progesterone receptor, p53, c-erbB-2, topoisomerase IIalpha 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 topoIIalpha 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.


CONCLUSIONS
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.
Mylona
Eleni
E
Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, GR-115 27 Athens, Greece.
Magkou
Christina
C
Giannopoulou
Ioanna
I
Agrogiannis
George
G
Markaki
Sofia
S
Keramopoulos
Antonios
A
Nakopoulou
Lydia
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019717:Tissue Inhibitor of Metalloproteinase-3; D016159:Tumor Suppressor Protein p53