Human breast cancer MCF-7 cell line contains inherently drug-resistant subclones with distinct genotypic and phenotypic features.
The resistance of cancer cells to multiple chemotherapeutic agents poses a major problem in the successful treatment of breast cancer. Whether drug resistance is due to changes induced in the drug-exposed tumor cells or represents the selective growth of one or more drug-resistant clones present in the initial tumor remains controversial. Here we provide evidence that the development of multidrug resistance in a human breast cancer cell line (MCF-7) is a result of propagation of an inherently resistant subclone. The drug-resistant MCF-7 (MCF-7/DOX) cells exhibited several phenotypic and genotypic features that were notably distinct from those observed in the parental drug-sensitive (MCF-7/WT) cells. The most striking change was the presence of a full-length functional caspase-3 in MCF-7/DOX cells that was missing in the parental MCF-7/WT cells due to a deletion mutation in the caspase-3 gene. A drug-resistant MCF-7 cell subline (MCF-7/WT/DOX) was established by exposing the MCF-7/WT cells directly to a high dose of doxorubicin and used for determining the phenotypic and genotypic alterations associated with drug resistance. The MCF-7/WT/DOX cells exhibited alterations identical to those of the MCF-7/DOX cells but which were strikingly distinct from the parental MCF-7/WT cell line. These results suggest that drug resistance is an inherent property of some cancer cells that are present in the initial tumor burden and exhibit distinct phenotypic/genotypic alterations.
Devarajan
Eswaran
E
Department of Bioimmunotherapy, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Chen
Jack
J
Multani
Asha S
AS
Pathak
Sen
S
Sahin
Aysegul A
AA
Mehta
Kapil
K
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002871:Chromosome Banding; D002875:Chromosomes / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007621:Karyotyping; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine