Multidrug resistance-associated protein (MRP1) is overexpressed in DNA aneuploid carcinomatous cells in non-small cell lung cancer (NSCLC).
Resistance to chemotherapy is intrinsically present in most nonsmall-cell lung carcinomas (NSCLC). No parameter has yet been determined to predict the response to chemotherapy. However, MRP1 (multidrug resistance-associated protein) is suspected to play an important role in resistance to treatment. The genetic basis for this resistance is not clearly understood, but it could result from chromosome reassortments catalyzed by aneuploidy. The aim of this study was to investigate MRP1 expression concurrently to DNA ploidy analysis in order to evaluate the link between MRP1 expression and chromosome 16 (MRP1 gene location) aberrations in NSCLC before treatment. Eighty-four surgical tumor specimens, 18 selected samples containing more than 80% of carcinomatous cells and 11 samples from normal bronchial epithelium were studied. Samples were stained by MRP1 FITC indirect staining and propidium iodide and analyzed by Flow Cytometry. Fifty tumors contained at least 1 DNA-aneuploid clone and the percentage of MRP1-positive cells was higher in DNA-aneuploid cells (p = 0.0003). All tumors expressed MRP1, but the level of expression was 3-fold higher in DNA-aneuploid cells than in DNA-diploid cells (normal bronchial cells as well as carcinomatous cells) (p < 0.0001). FISH analysis of 24 tumor imprints using a chromosome 16 alpha-satellite centromere probe demonstrated significantly more frequent gain of chromosome 16 in DNA-aneuploid tumors. These results suggest that MRP1 overexpression in NSCLC could be a consequence of chromosome 16 reassortments catalyzed by aneuploidy and that DNA-aneuploid tumors could require different treatment modalities from those applied to DNA-diploid tumors.
Service d'Histologie et Biologie Tumorale, Hôpital Tenon (AP-HP), and UPRES 3499, Université Paris VI, France.
Hélène
H
Doubre
Danièle
D
Césari
Alexa
A
Mairovitz
Cécile
C
Bénac
Sandra
S
Chantot-Bastaraud
Koami
K
Dagnon
Martine
M
Antoine
Claire
C
Danel
Jean-François
JF
Bernaudin
Jocelyne
J
Fleury-Feith
D000782:Aneuploidy; D001980:Bronchi / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D002503:Centromere / Q000235:genetics; D002869:Chromosome Aberrations; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D004276:DNA, Satellite / Q000235:genetics; D004171:Diploidy; D018432:Drug Resistance, Multiple; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*
D004273:DNA, Neoplasm; D004276:DNA, Satellite; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1