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Protease nexin-1 expression is altered in human breast cancer.

ABSTRACT: BACKGROUND:Urokinase-type Plasminogen Activator (uPA), a serine protease, plays a pivotal role in human breast cancer metastasis by mediating the degradation of extracellular matrix proteins and promoting cell motility. In more advanced breast cancers, uPA activity is significantly up regulated and serves as a prognostic indicator of poor patient outcome. Classically, regulation of uPA activity, especially in breast cancers, is thought to be mediated by Type 1 Plasminogen Activator Inhibitor (PAI-1). However, we have recently found that a lesser known natural inhibitor of uPA, Protease Nexin 1 (PN-1), is expressed in normal human mammary tissue. Based on this observation, we investigated if PN-1 is also expressed in human breast cancers where it may contribute to the regulation of uPA and participate in the development of a metastatic phenotype. RESULTS:Using quantitative real-time PCR analysis, we measured PN-1 mRNA expression in tissues obtained from 26 human breast tumor biopsies and compared these values with those obtained from 10 normal breast tissue samples. Since both PAI-1 and uPA expression levels are known to be elevated in metastatic breast cancer, we also measured their levels in our 26 tumor samples for direct comparison with PN-1 expression. We found that PN-1 expression was elevated over that found in normal mammary tissue; an increase of 1.5- to 3.5-fold in 21 of 26 human breast tumors examined. As anticipated, both PAI-1 and uPA mRNA levels were significantly higher in the majority of breast tumors; 19 of 26 tumors for PAI-1 and 22 of 26 tumors for uPA. A quantile box plot of these data demonstrates that the elevated PN-1 expression in breast tumor tissues directly correlates with the increased expression levels found for PAI-1 and uPA. CONCLUSION:The fact that PN-1 expression is elevated in human breast cancer, and that its increased expression is directly correlated with increases measured for PAI-1 and uPA, suggests that PN-1 may contribute to the regulation of uPA-mediate tumor cell motility and metastatic spread.

SUBMITTER: Candia BJ

PROVIDER: S-EPMC1501059 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Protease nexin-1 expression is altered in human breast cancer.

Candia Britny J BJ Hines William C WC Heaphy Christopher M CM Griffith Jeffrey K JK Orlando Robert A RA

Cancer cell international 20060531

<h4>Background</h4>Urokinase-type Plasminogen Activator (uPA), a serine protease, plays a pivotal role in human breast cancer metastasis by mediating the degradation of extracellular matrix proteins and promoting cell motility. In more advanced breast cancers, uPA activity is significantly up regulated and serves as a prognostic indicator of poor patient outcome. Classically, regulation of uPA activity, especially in breast cancers, is thought to be mediated by Type 1 Plasminogen Activator Inhib ...[more]

PMID: 16737540

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Project description:An increase in the expression of estrogen receptors (ER) and the expanded population of ER-positive cells are two common phenotypes of breast cancer. Detection of the aberrantly expressed ER? in breast cancer is carried out using ER?-antibodies and radiolabelled ligands to make decisions about cancer treatment and targeted therapy. Capitalizing on the beneficial advantages of aptamer over the conventional antibody or radiolabelled ligand, we have identified a DNA aptamer that selectively binds and facilitates the detection of ER? in human breast cancer tissue sections. The aptamer is identified using the high throughput sequencing assisted SELEX screening. Biophysical characterization confirms the binding and formation of a thermodynamically stable complex between the identified DNA aptamer (ERaptD4) and ER? (Ka = 1.55±0.298×108 M(-1); ?H = 4.32×104±801.1 cal/mol; ?S = -108 cal/mol/deg). Interestingly, the specificity measurements suggest that the ERaptD4 internalizes into ER?-positive breast cancer cells in a target-selective manner and localizes specifically in the nuclear region. To harness these characteristics of ERaptD4 for detection of ER? expression in breast cancer samples, we performed the aptamer-assisted histochemical analysis of ER? in tissue samples from breast cancer patients. The results were validated by performing the immunohistochemistry on same samples with an ER?-antibody. We found that the two methods agree strongly in assay output (kappa value = 0.930, p-value <0.05 for strong ER? positive and the ER? negative samples; kappa value = 0.823, p-value <0.05 for the weak/moderate ER+ve samples, n = 20). Further, the aptamer stain the ER?-positive cells in breast tissues without cross-reacting to ER?-deficient fibroblasts, adipocytes, or the inflammatory cells. Our results demonstrate a significant consistency in the aptamer-assisted detection of ER? in strong ER? positive, moderate ER? positive and ER? negative breast cancer tissues. We anticipate that the ERaptD4 aptamer targeting ER? may potentially be used for an efficient grading of ER? expression in cancer tissues.

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Protease nexin-1 expression is altered in human breast cancer.

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Protease nexin-1 expression is altered in human breast cancer.

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