Gene expression and amplification in breast carcinoma cells with intrinsic and acquired doxorubicin resistance

Abstract

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 Pglycoprotein 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 identi®ed which included several keratins, in particular keratins 8 and 18 which are regulated through the ras signalling pathway. Analysis of genomic ampli®cations and deletions revealed speci®c genetic alterations common to both intrinsic and acquired DOX resistance including ABCB1, PGY3 (ABCB4) and BAK. The ®ndings shown here indicate new possibilities for the diagnosis of DOX resistance using gene expression, and potential novel therapeutic targets for pharmacological intervention. Oncogene (2001) 20, 1300 ± 1306.

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

“…The association of increased expression of MDR1 and increased copy number has been reported in acquired paclitaxel-resistant ovarian cancer cell lines 24 and doxorubicin-resistant breast cancer cell lines, 25 and perhaps not surprisingly, the co-upregulation of MDR3 is frequently observed when MDR1 expression is driven by gene amplification. 24,25 The drugs used to produce resistance phenotypes in these studies are effluxed from cells by the MDR1 transporter, evidencing the selective advantage bestowed by MDR1 upregulation. The data generated using MiaPaCa BCRP further demonstrate that resistance to AZD1152 HQPA can be achieved through a second genetic route: the upregulation of BCRP.…”

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

“…Both chromosome 7 alterations and several cytogenetic changes involving the 7q21 locus are associated with the development of MDR in sarcoma cells (Chen et al, 2002). Analysis of genomic amplifications and deletions revealed specific genetic alterations common to both intrinsic and acquired doxorubicin resistance including ABCB1, PGY3 (ABCB4) and BAK (Turton et al, 2001).…”

Alteration of Genomic Responses to Doxorubicin and Prevention of MDR in Breast Cancer Cells by a Polymer Excipient: Pluronic P85

“…18 The level of Pgp in MCF7/Dox cells was determined by Western blot analysis. Importantly, increases in the level of Pgp detected in the cells showed a strong correlation with the increase in the amount of Dox tolerated by the cells in the culture media (Figure 2).…”