Abstract
BackgroundHSP90 may be a favorable target for investigational therapy in breast cancer. In fact, the HSP90 inhibitor, 17AAG, currently has entered in phase II clinical trials as an anticancer agent in breast and other tumors. Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple pathways we applied global analysis using gene array technology to study new genes and pathways involved in the drug response in breast cancer.MethodsGene expression profiling using Whole Human Genome Agilent array technology was applied to a total of six sensitive and two resistant breast cancer cell lines pre-treatment and treated with the 17AAG for 24 and 48 hours.ResultsWe have identified a common molecular signature of response to 17AAG composed of 35 genes which include novel pharmacodynamic markers of this drug. In addition, different patterns of HSP90 client transcriptional changes after 17AAG were identified associated to the sensitive cell lines, which could be useful to evaluate drug effectiveness. Finally, we have found differentially expressed pathways associated to resistance to 17AAG. We observed significant activation of NF-κB and MAPK pathways in resistant cells upon treatment, indicating that these pathways could be potentially targeted to overcome resistance.ConclusionsOur study shows that global mRNA expression analysis is a useful strategy to examine molecular effects of drugs, which allowed us the discovery of new biomarkers of 17AAG activity and provided more insights into the complex mechanism of 17AAG resistance.
Highlights
HSP90 may be a favorable target for investigational therapy in breast cancer
Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple signaling pathways, expression signatures have been developed to understand the mechanisms of drug action and to predict the sensitivity to treatment
We investigated the biology underlying the differential gene expression across breast cancer cell lines treated with HSP90 inhibitor, 17AAG
Summary
The HSP90 inhibitor, 17AAG, currently has entered in phase II clinical trials as an anticancer agent in breast and other tumors. Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple pathways we applied global analysis using gene array technology to study new genes and pathways involved in the drug response in breast cancer. Preclinical studies have demonstrated sensitivity of HER2+ tumors to HSP90 inhibitor [2,3,4], lately though it was demonstrated that HSP90 is a very effective target of therapy in triple. Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple signaling pathways, expression signatures have been developed to understand the mechanisms of drug action and to predict the sensitivity to treatment. Gene expression and proteomic profiling studies have been done previously in a panel of ovarian and colon cancer cell lines after 17AAG treatment [24,25] and in pancreatic cancer after treatment with 17AAG partner, IPI 504 [26], there are no previous studies focused in breast tumors under 17AAG treatment
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