Abstract and Introduction
Abstract
The recognition of subtypes of breast carcinomas based on their molecular features has brought new perspectives in breast cancer research. Some key regulators of angiogenesis and tumor infiltration were evaluated in breast carcinomas of basal phenotype (cytokeratin [CK]5+). Immunohistochemical analysis with 14 primary antibodies was performed in 100 formalin-fixed, paraffin-embedded samples of invasive ductal carcinomas. CK5 correlated with indicators of poor outcome, including precocious age, high histologic grade, lymph node positivity, advanced pathologic stage, negativity for hormonal receptors, and a high proliferative rate (Ki-67 labeling index). CK5 also correlated with vascular endothelial growth factor (VEGF) expression but not with the microvessel density. Considering that VEGF-overexpressing neoplastic mammary cells display increased proliferative activity in vitro regardless of the angiogenic effect of VEGF, the differential expression of VEGF might contribute to the more aggressive behavior of these neoplasms. CK5 correlated with tissue inhibitor of metalloproteinase (TIMP)-1, but not matrix metalloproteinase (MMP)-1, MMP-2, extracellular matrix metalloproteinase inducer, TIMP-2, or plasminogen activator inhibitor, indicating that antiproteolytic stimuli might be preponderant in these neoplasms.
Introduction
According to the molecular profile, sporadic breast carcinomas can be categorized into at least 5 subtypes: luminal subtype A, luminal subtype B, normal breast-like subtype, HER-2-overexpressing subtype, and basal-like subtype. There is a highly significant difference in overall survival and relapse-free survival between these subtypes, with the basal-like and HER-2+ subtypes associated with the poorest prognoses. The basal-like subtype is characterized by expression of the high-weight cytokeratins (CKs) such as CK5. According to the literature, about 17% to 37% of breast carcinomas have this phenotype. The biologic significance of the differential expression of CK polypeptides in breast carcinomas is unclear.
Tumoral progression followed by invasion and metastases occur owing to a complex interaction among several factors produced by the tumor and the response of the host. This process depends overall on the formation of new blood vessels (tumoral angiogenesis). The main stimulus for angiogenesis is the interaction between the vascular endothelial growth factor (VEGF) and its receptor.
To allow the neoformed vessels to infiltrate the stroma, tumoral cells must produce some proteinases, in which cathepsin D, plasminogen activator factor, and metalloproteinases 1, 2, 3, and 9 merit distinction. Furthermore, there is increasing evidence that these proteinases are activated by a cell surface glycoprotein known as extracellular matrix metalloproteinase inducer (EMMPRIN). In addition to these proteinases, tumoral cells also might produce inhibitory proteins, including tissue inhibitors of metalloproteinases (TIMPs) and plasminogen activator inhibitor (PAI). The ability of the neoformed vessels to infiltrate the tissues depends on the predominance of the proteinases or their inhibitors.
The role of angiogenesis and its interaction with the proteinases and their inhibitors in CK5+ mammary carcinomas is unknown. Therefore, we studied the relationship between the expression of CK5 and the key regulators of angiogenesis and tumor infiltration in human breast carcinomas and compared these data with the clinicopathologic features of prognostic significance.