Abstract
BackgroundUrokinase-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.ResultsUsing 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.ConclusionThe 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.
Highlights
Urokinase-type Plasminogen Activator, a serine protease, plays a pivotal role in human breast cancer metastasis by mediating the degradation of extracellular matrix proteins and promoting cell motility
The fact that Protease Nexin 1 (PN-1) expression is elevated in human breast cancer, and that its increased expression is directly correlated with increases measured for plasminogen activator inhibitor (PAI-1) and Urokinase-type Plasminogen Activator (uPA), suggests that PN-1 may contribute to the regulation of uPA-mediate tumor cell motility and metastatic spread
In order to test the specificity of these novel primers, we amplified the 81 bp PN-I sequence by straight RT-PCR using RNA purified from a normal human fibroblast cell line (HuFb) and compared the product to that obtained from amplification using the human PN-1 cDNA
Summary
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. We have recently found that a lesser known natural inhibitor of uPA, Protease Nexin 1 (PN-1), is expressed in normal human mammary tissue. An important characteristic of highly invasive tumor cells is an elevated capacity to degrade the surrounding extracellular matrix (ECM). Plasmin is a broad-spectrum protease that cleaves many ECM proteins, as well as activates certain matrix metalloproteinases [6] This proteolytic cascade enables highly migratory tumor cells to efficiently degrade their surrounding matrices, exit the primary site of tumor growth and colonize distant secondary sites [7]. In addition to its protease activity which augments breast tumor cell motility, high expression levels of uPA is a wellestablished prognostic indicator of poor patient outcome during the course of breast cancer [8,9]
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