期刊
MOLECULAR CANCER
卷 10, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1476-4598-10-135
关键词
aCGH; microRNA; gene expression; breast cancer; drug resistance
资金
- Ministry of Education, Culture, Sports, Science and Technology
- National Institute of Biomedical Innovation (NiBio)
- Takeda Science Foundation
- Japan Society for the Promotion of Science (JSPS)
- Grants-in-Aid for Scientific Research [10J04220] Funding Source: KAKEN
Background: Acquisition of drug-resistance in cancer has led to treatment failure, however, their mechanisms have not been clarified yet. Recent observations indicated that aberrant expressed microRNA (miRNA) caused by chromosomal alterations play a critical role in the initiation and progression of cancer. Here, we performed an integrated genomic analysis combined with array-based comparative hybridization, miRNA, and gene expression microarray to elucidate the mechanism of drug-resistance. Results: Through genomic approaches in MCF7-ADR; a drug-resistant breast cancer cell line, our results reflect the unique features of drug-resistance, including MDR1 overexpression via genomic amplification and miRNA-mediated TP53INP1 down-regulation. Using a gain of function study with 12 miRNAs whose expressions were down-regulated and genome regions were deleted, we show that miR-505 is a novel tumor suppressive miRNA and inhibits cell proliferation by inducing apoptosis. We also find that Akt3, correlate inversely with miR-505, modulates drug sensitivity in MCF7-ADR. Conclusion: These findings indicate that various genes and miRNAs orchestrate to temper the drug-resistance in cancer cells, and thus acquisition of drug-resistance is intricately controlled by genomic status, gene and miRNA expression changes.
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