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Expression of the multidrug resistance-associated protein (MRP) gene in primary non-small-cell lung cancer
K Nooter1, F T Bosman, H Burger
1Department of Medical Oncology, University Hospital Rotterdam and Rotterdam Cancer Institute, The Netherlands.
Background:
One of the major problems in the cure of advanced non-small-cell lung cancer (NSCLC) is its lack of response to cytotoxic drug treatment, and the mechanisms underlying this intrinsic drug resistance are unclear.
Patients And Methods:
We determined the expression of a newly recognised drug resistance gene, the Multidrug Resistance-associated Protein (MRP) gene, in normal lung tissue and in tumour biopsies from 35 surgically resected NSCLCs (11 adenocarcinomas, 24 squamous cell carcinomas). MRP mRNA levels were quantitated by RNase protection assay and expression of the MRP Mr 190,000 glycoprotein was estimated by immunohistochemistry.
Results:
Using the MRP-specific monoclonal antibody MRPr1, MRP expression was detected by immunohistochemistry in epithelial cells lining the bronchi in normal lung. In NSCLC approximately 35% of the samples showed elevated MRP mRNA levels. Based on MRP-specific immunohistochemical staining the tumours were divided into 4 groups: 12% were scored as negative (-), 14% showed weak cytoplasmic staining of the tumour cells (+/-), 40% had a clear cytoplasmic staining (+), and in 34% a strong cytoplasmic as well as membranous staining was observed (++). MRP expression, as estimated by immunohistochemistry, correlated with the MRP mRNA levels quantitated by RNase protection assay (correlation coefficient = 0.745, p = 0.0009), with MRP mRNA levels (mean +/- SD) of 3.0 +/- 1.0 U, 3.5 +/- 0.7 U, 7.5 +/- 5.9 U, and 19.3 +/- 10.7 U, in the (-), (+/-), (+), and (++) immunohistochemistry expression groups, respectively. Among the squamous cell carcinomas a correlation was observed between MRP staining and tumour cell differentiation: the strongest MRP staining was predominantly found in the well differentiated tumours.
Conclusions:
Hyperexpression of MRP is frequently observed in primary NSCLC, especially in the well differentiated squamous cell carcinomas. Further studies are needed to assess the role of MRP in the mechanism of clinical drug resistance in NSCLC.
Insights
Multidrug Resistance-associated Protein (MRP) gene is often overexpressed in non-small-cell lung cancer (NSCLC), particularly in well-differentiated squamous cell carcinomas. This finding may help explain NSCLC
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Advanced non-small-cell lung cancer (NSCLC) exhibits poor response to cytotoxic drugs.
- Mechanisms of intrinsic drug resistance in NSCLC remain largely unknown.
Purpose of the Study:
- To investigate the expression of the Multidrug Resistance-associated Protein (MRP) gene in NSCLC.
- To determine the correlation between MRP expression and drug resistance in NSCLC.
Main Methods:
- Expression analysis of MRP mRNA using RNase protection assay.
- Immunohistochemical assessment of MRP glycoprotein expression in tumor biopsies from 35 NSCLC patients.
- Correlation analysis between MRP mRNA levels and protein expression.
Main Results:
- MRP expression was detected in normal lung epithelium and NSCLC tissues.
- Approximately 35% of NSCLC samples showed elevated MRP mRNA levels.
- MRP expression, assessed by immunohistochemistry, correlated significantly with MRP mRNA levels (r=0.745, p=0.0009).
- Strongest MRP staining was observed in well-differentiated squamous cell carcinomas.
Conclusions:
- Hyperexpression of MRP is common in primary NSCLC, particularly in well-differentiated squamous cell carcinomas.
- Further research is required to elucidate the role of MRP in clinical drug resistance in NSCLC.