Multidrug resistance-associated protein (MRP1) is overexpressed in DNA aneuploid carcinomatous cells in non-small cell lung cancer (NSCLC)

Doubre, H.; Cesari, D.; Mairovitz, A.; Bénac, Cécile; Chantot‐Bastaraud, Sandra; Dagnon, Koami; Antoine, Martine; Danel, Claire; Bernaudin, Jean-François; Fleury‐Feith, Jocelyne

doi:10.1002/ijc.20617

Cited by 26 publications

(27 citation statements)

References 33 publications

(44 reference statements)

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“…Likewise, drug resistance is not a selective advantage for natural carcinogenesis in the absence of chemotherapy. Yet, a high percentage of cancers is a priori or intrinsically drug-resistant [127,128]. Moreover, the majority of the drug resistances associated with multidrug resistance offer no selective advantages against the drug that induced it.…”

Section: Nonselective Phenotypes Of Cancer Cellsmentioning

confidence: 99%

Aneuploidy and Cancer: From Correlation to Causation

Duesberg

Fabarius³

et al. 2006

Infection and Inflammation: Impacts on Oncogenesis

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Conventional genetic theories have failed to explain why cancer (1) is not found in newborns and thus not heritable; (2) develops only years to decades after 'initiation' by carcinogens; (3) is caused by non-mutagenic carcinogens; (4) is chromosomally and phenotypically 'unstable'; (5) carries cancer-specific aneuploidies; (6) evolves polygenic phenotypes; (7) nonselective phenotypes such as multidrug resistance, metastasis or affinity for non-native sites and 'immortality' that is not necessary for tumorigenesis; (8) contains no carcinogenic mutations. We propose instead that cancer is a chromosomal disease: Accordingly, carcinogens initiate chromosomal evolutions via unspecific aneuploidies. By unbalancing thousands of genes aneuploidy corrupts teams of proteins that segregate, synthesize and repair chromosomes. Aneuploidy is thus a steady source of karyotypic-phenotypic variations from which, in classical Darwinian terms, selection of cancer-specific aneuploidies encourages the evolution and subsequent malignant 'progressions' of cancer cells. The rates of these variations are proportional to the degrees of aneuploidy, and can exceed conventional mutation by 4-7 orders of magnitude. This makes cancer cells new cell 'species' with distinct, but unstable karyotypes, rather than mutant cells. The cancer-specific aneuploidies generate complex, malignant phenotypes, through the abnormal dosages of the thousands of genes, just as trisomy 21 generates Down syndrome. Thus cancer is a chromosomal rather than a genetic disease. The chromosomal theory explains (1) nonheritability of cancer, because aneuploidy is not heritable; (2) long 'neoplastic latencies' by the low probability of evolving competitive new species; (3) nonselective phenotypes via genes hitchhiking on selective chromosomes, and (4) 'immortality', because chromosomal variations neutralize negative mutations and adapt to inhibitory conditions much faster than conventional mutation. Based on this article a similar one, entitled 'The chromosomal basis of cancer', has since been published by us in Cellular Oncology 2005;27:293-318. Copyright © 2006 S. Karger AG, Basel Despite over 100 years of cancer research, the cause of cancer is still a matter of debate . We propose here that the problem of cancer is still

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Section: Nonselective Phenotypes Of Cancer Cellsmentioning

confidence: 99%

Aneuploidy and Cancer: From Correlation to Causation

Duesberg

Fabarius³

et al. 2006

Infection and Inflammation: Impacts on Oncogenesis

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“…Cytospin preparations of normal bronchial cells and A549 cells were prepared for immunocytochemistry, whereas touch prints were used for tumor cells from NSCLC samples, as previously described (Doubre et al 2005). Slides were air dried overnight at room temperature, rehydrated with PBS for 5 min, and fixed by paraformaldehyde (PFA, 0.5% in PBS, pH 7.4, 25 min at room temperature).…”

Section: Immunocytochemistry and Confocal Microscopy Analysismentioning

confidence: 99%

“…This index was used for semiquantitative evaluation of LRP cell expression in cell types and to compare the levels of LRP expression in DNA diploid vs DNA aneuploid cells, as previously described (Doubre et al 2005). DNA ploidy and S-phase data were analyzed using Wincycle software (Phoenix; San Diego, CA).…”

Section: Flow Cytometry Analysesmentioning

confidence: 99%

“…DNA ploidy was classified using a DNA index (DI), i.e., the ratio of the channel peaks between the studied cell population and the diploid cells. A sample was defined as DNA diploid when all the cell population has a DI between 0.95 and 1.05 and DNA aneuploid when at least one cell population with DI #0.95 or $1.05 was observed in at least 5% of the cells (Doubre et al 2005).…”

Section: Flow Cytometry Analysesmentioning

confidence: 99%

“…Moreover, as a recent study from our laboratory showed that DNA aneuploid carcinomatous cells from NSCLC with an increased chromosome 16 number, harboring the mrp1 locus (16p13.1) close to the lrp locus (16p11.2), exhibited higher MRP1 expression than DNA diploid cells (Doubre et al 2005), we therefore hypothesized that MRP1 and LRP could have a coordinate expression. We also investigated the potential role of the number of lrp gene copies on the level of LRP expression in NSCLC cancer cells.…”

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confidence: 91%

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Immunolocalization and Cell Expression of Lung Resistance-related Protein (LRP) in Normal and Tumoral Human Respiratory Cells

Bouhamyia

Chantot‐Bastaraud

Zaïdi

et al. 2007

J Histochem Cytochem.

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Lung resistance-related protein (LRP) is an integral part of the multidrug resistance (MDR) phenotype involved in cell resistance toward xenobiotics or chemotherapy. The aim of this study was to compare the intracellular localization and cell expression of LRP in normal bronchial cells and their tumoral counterparts from non-small cell lung cancer (NSCLC). LRP expression was also investigated concurrently with DNA ploidy and chromosome 16 ( lrp gene locus) aberrations. Confocal microscopy showed that LRP localization was exclusively intracytoplasmic regardless of the cell type and was never observed in the nuclear pore complex. Flow cytometry demonstrated a similar level of LRP expression in normal bronchial cells and in cancer cells from NSCLC samples. FISH analysis, performed to evaluate the number of chromosome 16 and lrp loci, demonstrated a significant gain of chromosome 16 in DNA aneuploid tumors. Furthermore, we did not find any link between LRP expression and DNA ploidy status or chromosome 16 number. These results suggest that LRP expression observed in NSCLC, maintained through the carcinogenesis process of respiratory cells, is not altered by the increased number of copies of chromosome 16 and probably controlled by mechanisms different from those of MRP1 expression, whereas both proteins are associated with the MDR phenotype. (J Histochem Cytochem 55: 773–782, 2007)

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ABC Proteins and Oncology: Expression, Detection, and Implication of ABC Proteins in Solid Tumors

Bernaudin

Fajac

Fleury‐Feith

et al. 2009

ABC Transporters and Multidrug Resistance

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Multidrug resistance-associated protein (MRP1) is overexpressed in DNA aneuploid carcinomatous cells in non-small cell lung cancer (NSCLC)

Abstract: Resistance to chemotherapy is intrinsically present in most nonsmall-cell lung carcinomas (NSCLC).

Cited by 26 publications

References 33 publications

Aneuploidy and Cancer: From Correlation to Causation

Aneuploidy and Cancer: From Correlation to Causation

Immunolocalization and Cell Expression of Lung Resistance-related Protein (LRP) in Normal and Tumoral Human Respiratory Cells

ABC Proteins and Oncology: Expression, Detection, and Implication of ABC Proteins in Solid Tumors

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