Gene expression and amplification in breast carcinoma cells with intrinsic and acquired doxorubicin resistance.
The multidrug resistance (MDR) phenotype is a major cause of cancer treatment failure. Here the expressions of 4224 genes were analysed for association with intrinsic or acquired doxorubicin (DOX) resistance. A cluster of overexpressed genes related to DOX resistance was observed. Included in this cluster was ABCB1 the P-glycoprotein transporter protein gene and MMP1 (Matrix Metalloproteinase 1), indicative of the invasive nature of resistant cells, and the oxytocin receptor (OXTR), a potential new therapeutic target. Overexpression of genes associated with xenobiotic transformation, cell transformation, cell signalling and lymphocyte activation was also associated with DOX resistance as was estrogen receptor negativity. In all carcinoma cells, compared with HBL100 a putatively normal breast epithelial cell line, a cluster of overexpressed genes was identified which included several keratins, in particular keratins 8 and 18 which are regulated through the ras signalling pathway. Analysis of genomic amplifications and deletions revealed specific genetic alterations common to both intrinsic and acquired DOX resistance including ABCB1, PGY3 (ABCB4) and BAK. The findings shown here indicate new possibilities for the diagnosis of DOX resistance using gene expression, and potential novel therapeutic targets for pharmacological intervention.
Turton
N J
NJ
MRC Toxicology Unit, University of Leicester, Lancaster Road, Leicester, LE1 9HN UK.
Judah
D J
DJ
Riley
J
J
Davies
R
R
Lipson
D
D
Styles
J A
JA
Smith
A G
AG
Gant
T W
TW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006801:Humans; D010641:Phenotype; D011960:Receptors, Estrogen / Q000032:analysis
D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D004317:Doxorubicin