Invasion Factors uPA/PAI-1 and HER2 Status Provide Independent and Complementary Information on Patient Outcome in Node-Negative Breast Cancer

Zemzoum, Iris; Kates, Ronald; Ross, Jeffrey S.; Dettmar, P.; Dutta, Moshumi; Henrichs, Cordula; Yurdseven, Suna; Höfler, Heinz; Kiechle, Marion; Harbeck, Nadia

doi:10.1200/jco.2003.04.170

Cited by 96 publications

(62 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Gene ablation and reconstitution data show that PAI1 can promote cancer progression (11)(12)(13)(14), and correlative data consistently indicate that its elevated expression in breast tumors is an independent indicator of poor prognosis (4)(5)(6)(7)(8). Here, we found that high PAI1 mRNA expression is also associated with shorter overall survival in breast cancer.…”

Section: Discussionsupporting

confidence: 56%

“…Data sets that used a Research Genetics cDNA platform were excluded based on evidence that the PAI1 clone in this set does not match the PAI1 sequence. 8 The UCSF data set contained expression profiles from Affymetrix HG-U133A arrays run on 118 breast cancers as well as genomic copy number information obtained by array-based comparative genomic hybridization (CGH). The Miller data set was obtained through the Gene Expression Omnibus (accession no.…”

Section: Study Populationsmentioning

confidence: 99%

“…High tumoral PAI1 protein expression is associated with poor survival in several forms of cancer (1)(2)(3) and is a strong independent prognostic factor in breast cancer, with elevated levels forecasting shorter recurrence-free and overall survival (4)(5)(6)(7)(8). In addition, prospective data suggest that high tumoral PAI1 levels can identify those lymph node-negative (LN − ) breast cancer patients who are most likely to benefit from adjuvant chemotherapy (9,10).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression

Sternlicht¹,

Dunning

Moore

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Plasminogen activator inhibitor-1 (PAI1) can promote cancer progression, and its protein expression in tumors is an independent indicator of poor prognosis in many forms of cancer. Here, we show that high PAI1 mRNA levels also predict for shorter overall survival in two independent breast cancer data sets, highlighting the importance of its transcriptional regulation. The −675insG (4G/5G) singlenucleotide polymorphism in the PAI1 gene promoter has been shown to influence PAI1 transcription, with the 4G allele eliciting higher reporter gene expression in vitro and higher levels of circulating PAI1 in vivo. Nevertheless, its genotypic distribution in 2,539 British women with invasive breast cancer was virtually identical to that seen in 1,832 matched controls (P = 0.72), and annual mortality rates for 4G4G, 4G5G, and 5G5G cases were 2.6%, 2.8%, and 3.1% per year, respectively (P = 0.10). Thus, there was no association with breast cancer incidence or outcome, and in a separate set of breast cancers, the 4G/5G single-nucleotide polymorphism showed no association with PAI1 mRNA expression (P = 0.85). By contrast, connective tissue growth factor (CTGF), which can regulate PAI1 expression in culture, was associated with PAI1 expression in three independent cohorts (P ≪ 0.0001). In addition, PAI1 gene copy number differences in the tumors were correlated with PAI1 mRNA expression (P = 0.0005) and seemed to affect expression independently of CTGF. Thus, local factors, such as CTGF and genomic amplification, seem to be more important than germ line genetic variation in influencing PAI1 expression and its untoward effects in breast cancer.Requests for reprints:

show abstract

Section: Discussionsupporting

confidence: 56%

Section: Study Populationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression

Sternlicht¹,

Dunning

Moore

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

show abstract

“…With reference to the National Institutes of Health (28) and the St. Gallen consensus guidelines (29), up to 90% of LN-negative breast cancer patients are eligible to receive adjuvant systemic chemotherapy. By use of uPA and PAI-1 as additional prognostic factors, subgroups of LN-negative patients at high or low risk can be identified (30)(31)(32)(33)(34)(35)(36). Patients at high risk, as identified by elevated uPA and/or PAI-1 protein levels, benefit from adjuvant systemic chemotherapy, resulting in a substantial reduction of risk of relapse (1,31).…”

Section: Discussionmentioning

confidence: 99%

Quantitative RT-PCR assays for the determination of urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 mRNA in primary tumor tissue of breast cancer patients: Comparison to antigen quantification by ELISA

Biermann

Holzscheiter²,

Kotzsch³

et al. 2008

Int J Mol Med

Self Cite

View full text Add to dashboard Cite

Abstract. Urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) play a key role in tumor-associated processes such as the degradation of extracellular matrix proteins, tissue remodeling, cell adhesion, migration, and invasion. High antigen levels of uPA and PAI-1 in tumor tissue of various solid malignant tumors, including breast cancer, are associated with poor patient prognosis. In the present study, we examined whether analysis of uPA and PAI-1 mRNA expression represents an alternative to the measurement of the respective antigen levels in breast cancer. Highly sensitive quantitative real-time PCR (QPCR) assays, based on the LightCycler technology, were established to quantify uPA and PAI-1 mRNA expression in breast cancer cell lines as well as in tumor tissue of breast cancer patients. mRNA concentrations were normalized to the expression level of the housekeeping gene h-G6PDH. The respective uPA and PAI-1 antigen concentrations were determined by established ELISA formats. QPCR mean interassay variation coefficients were 11% (uPA) and 8% (PAI-1). In breast cancer cell lines, mRNA and antigen values were highly correlated for both uPA and PAI-1 (each: r s =0.95; p<0.001). In contrast, correlations between uPA/PAI-1 mRNA and protein in the breast cancer samples were found to be distinctly weaker or not significant. Thus, quantitative determination of mRNA expression for both factors does not mirror antigen levels in breast cancer tissue, possibly due to posttranscriptional regulation. Except for nodal status being inversely correlated with uPA mRNA levels, no significant interrelations were observed between uPA or PAI-1 mRNA expression and clinicopathological parameters. On the protein level, elevated uPA and PAI-1 values were associated with a negative steroid hormone receptor status. In conclusion, the implementation of mRNA quantification of uPA and PAI-1 in breast tumors is unable to serve as a one-to-one substitution for antigen determination by ELISA.

show abstract

“…The study by Urban et al indicates that overexpression of uPA mRNA levels in HER-2 positive breast cancer determines a worse outcome of the disease [30]. On the other hand, Harbeck et al demonstrated that uPA/PAI-1 and HER-2 gave independent information on disease-free survival in lymph node-negative breast cancer patients [31] with a similar finding described by Konecny et al [32] and by Zemzuoum et al [33]. Therefore, uPA and PAI-1 levels might, independently of HER-2 status, help us to better select patients that will benefit from anthracyclines.…”

Section: Discussionmentioning

confidence: 53%

High levels of uPA and PAI-1 predict a good response to anthracyclines

Borštnar

Sadikov

Možina

et al. 2009

Breast Cancer Res Treat

View full text Add to dashboard Cite

Invasion Factors uPA/PAI-1 and HER2 Status Provide Independent and Complementary Information on Patient Outcome in Node-Negative Breast Cancer

Cited by 96 publications

References 23 publications

Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression

Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression

Quantitative RT-PCR assays for the determination of urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 mRNA in primary tumor tissue of breast cancer patients: Comparison to antigen quantification by ELISA

High levels of uPA and PAI-1 predict a good response to anthracyclines

Contact Info

Product

Resources

About