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Genomic Analysis of Etoposide Resistance Reveals Multiple Alterations of Gene and microRNA Expression
Author(s) -
Moitra Karobi,
McGee Kate,
Sawitzke Julie,
Yuhki Naoya,
Robey Rob,
Bates Susan,
Dean Michael
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.924.4
Subject(s) - downregulation and upregulation , gene knockdown , biology , microrna , gene expression profiling , cancer research , gene expression , abcc1 , microarray analysis techniques , drug resistance , gene , atp binding cassette transporter , genetics , transporter
In order to develop targeted therapeutic strategies to combat drug resistance it is essential to understand the basic molecular mechanisms through which cancer cells control sensitivity to chemotherapeutics. To identify new candidate genes and facilitate the discovery of novel drug resistance pathways we generated differential gene expression profiles of etoposide resistant and sensitive MCF7 breast cancer cells using Affymetrix U133 plus 2 high‐density microarrays. Differential expression of over 4000 genes indicated that several drug resistance mechanisms are operating in etoposide resistant breast cancer cells including upregulation of ABC transporter genes ( ABCC1 & ABCC6 ), upregulation of DNA repair pathway genes ( p21, GADD45 & STAT1 ) and downregulation of apoptotic pathway genes ( CASP7, DIABLO etc). Transcription factors SOX9 & RUNX2 were upregulated in the drug resistant cells, suggesting their role in etoposide induced drug resistance. RUNX2 knockdown in the resistant cells increased sensitivity to etoposide and upregulated expression of pro‐apoptotic genes. MicroRNA arrays revealed differential expression of miRNA's in the cells lines. We found that miR‐218 mimic could downregulate the expression of ABCC6 in drug resistant cells indicating it's potential as a therapeutic agent to circumvent drug resistance. This research was supported by the Intramural Research Program of the NIH, NCI.