Protein and mRNA expression of uPAR and PAI-1 in myoepithelial cells of early breast cancer lesions and normal breast tissue

Abstract

Myoepithelial cells (MEs), which surround ducts and acini of the breast glands, exhibit an anti-invasive phenotype and form a natural border separating proliferating tumour cells of ductal carcinoma in situ (DCIS) from basement membrane (bm) and underlying stroma. Invasion requires penetration of these host cellular and extracellular matrix barriers. This destruction is caused by proteolytic activity of tumour cells and host bystander cells. There is substantial evidence that high concentrations of the urokinase plasminogenactivating system are conducive to tumour cell spread and metastasis. Prompted by the conspicuous absence of studies examining the role of the ME in breast cancer progression, we studied the expression of the urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor type-1 (PAI-1) in MEs of 60 DCIS samples. Our results show that nearly all MEs of DCIS and normal breast glands exhibit the uPAR antigen, whereas the PAI-1 antigen was mainly expressed in MEs of high-grade DCIS. In one intermediate DCIS numerous ducts showed an incomplete myoepithelial layer expressing uPAR and PAI-1. We conclude that uPAR in MEs may be necessary to attach them to the bm by uPAR/vitronectin (Vn) interaction. The strong expression of PAI-1, which is known to resolve the uPAR/Vn binding, may be involved in the detachment of MEs of DCIS. Although the role of PAI-1 acting as cell detachment factor could not be demonstrated in our study, we speculate that the loss of the anti-invasive ME layer in DCIS may be triggered by PAI-1 and could be an early sign of subsequent tumour cell infiltration.

Stromal cells associated with early invasive foci in human mammary ductal carcinoma in situ coexpress urokinase and urokinase receptor

“…This notion is consistent with the ultrastructural study of uPAR in colon cancer by Ohtani et al, 39 who reported that uPAR immunoreactivity was located along the plasma membrane of macrophages, whereas the immunoreactivity in fibroblasts was located in the rough endoplasmic reticulum. Our finding that uPAR immunoreactivity is only sporadically seen in myoepithelial cells disagrees with a recent study by Hildenbrand and Arens, 40 reporting that nearly all myoepithelial cells in DCIS as well as in normal breast glands express uPAR. These authors employed 3 different antibodies raised against uPAR for immunohistochemistry and an antisense DNA oligo for in situ hybridization.…”

Downregulation of the Ubiquitin-E3 Ligase RNF123 Promotes Upregulation of the NF-κB1 Target SerpinE1 in Aggressive Glioblastoma Tumors

“…Induction of uPAR/SerpinE1 expression by sphingosine-1-phosphate and interleukin-1 has been shown to promote the invasiveness of U373 glioblastoma cell lines [26]. Studies have shown a strong correlation between SerpinE1 expression and poor prognosis in different types of solid tumors [22,[27][28][29][30][31][32][33] as well as GB [34][35][36]. Moreover, increased serum levels of SerpinE1 were associated with poor survival in patients with high-grade gliomas, suggesting SerpinE1 utility as a blood marker [37].…”

Microenvironmental regulation of cancer development

“…Tumor myoepithelial cells were also unable to influence the polarity of breast epithelial cells in 3-dimensional collagen cultures due to their lack of production of BM constituent laminin 1 [70]. Myoepithelial cells of high grade DCIS exhibit strong expression of PAI-1 (plasminogen activator inhibitor type-1), which may resolve the interaction between uPAR (urokinase plasminogen activator receptor) present on the myoepithelium and vitronectin in the BM, and result in the detachment of the myoepithelial cells from the BM followed by tumor cell infiltration [71]. More importantly, tumor-associated myoepithelial cells express higher levels of several BM-degrading enzymes including MMPs, compared to their normal counterparts [36].…”