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Integrative "omic" analysis for tamoxifen sensitivity through cell based models.

Weng L, Ziliak D, Lacroix B, Geeleher P, Huang RS - PLoS ONE (2014)

Bottom Line: We identified 50 SNPs that associate with cellular sensitivity to endoxifen through their effects on 34 genes and 30 microRNA expression.Some of these findings are shared in both Caucasian and African samples, while others are unique in the African samples.Our integrative omic analysis facilitated the discovery of pharmacogenomic biomarkers that potentially affect tamoxifen sensitivity.

View Article: PubMed Central - PubMed

Affiliation: Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT
It has long been observed that tamoxifen sensitivity varies among breast cancer patients. Further, ethnic differences of tamoxifen therapy between Caucasian and African American have also been reported. Since most studies have been focused on Caucasian people, we sought to comprehensively evaluate genetic variants related to tamoxifen therapy in African-derived samples. An integrative "omic" approach developed by our group was used to investigate relationships among endoxifen (an active metabolite of tamoxifen) sensitivity, SNP genotype, mRNA and microRNA expressions in 58 HapMap YRI lymphoblastoid cell lines. We identified 50 SNPs that associate with cellular sensitivity to endoxifen through their effects on 34 genes and 30 microRNA expression. Some of these findings are shared in both Caucasian and African samples, while others are unique in the African samples. Among gene/microRNA that were identified in both ethnic groups, the expression of TRAF1 is also correlated with tamoxifen sensitivity in a collection of 44 breast cancer cell lines. Further, knock-down TRAF1 and over-expression of hsa-let-7i confirmed the roles of hsa-let-7i and TRAF1 in increasing tamoxifen sensitivity in the ZR-75-1 breast cancer cell line. Our integrative omic analysis facilitated the discovery of pharmacogenomic biomarkers that potentially affect tamoxifen sensitivity.

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Related in: MedlinePlus

Scatter plot of endoxifen sensitivity in YRI LCLs.X axis represents the 4 treatment concentrations of endoxifen (3, 5, 7 and 10 μM) and Y axis represents percent viable cells 72 hours after drug treatment. The table underneath shows median value and data range at each treatment condition.
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pone-0093420-g001: Scatter plot of endoxifen sensitivity in YRI LCLs.X axis represents the 4 treatment concentrations of endoxifen (3, 5, 7 and 10 μM) and Y axis represents percent viable cells 72 hours after drug treatment. The table underneath shows median value and data range at each treatment condition.

Mentions: As expected, a dose-dependent cellular growth inhibition was observed with increasing concentrations of endoxifen treatment in YRI LCLs, with median percent viable cells decreased from 88% to 56% after 3 and 10 uM endoxifen 72 hours treatment. Moreover, the inter-individual variations appear to be larger at higher treatment concentrations, as shown in Figure 1.


Integrative "omic" analysis for tamoxifen sensitivity through cell based models.

Weng L, Ziliak D, Lacroix B, Geeleher P, Huang RS - PLoS ONE (2014)

Scatter plot of endoxifen sensitivity in YRI LCLs.X axis represents the 4 treatment concentrations of endoxifen (3, 5, 7 and 10 μM) and Y axis represents percent viable cells 72 hours after drug treatment. The table underneath shows median value and data range at each treatment condition.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974759&req=5

pone-0093420-g001: Scatter plot of endoxifen sensitivity in YRI LCLs.X axis represents the 4 treatment concentrations of endoxifen (3, 5, 7 and 10 μM) and Y axis represents percent viable cells 72 hours after drug treatment. The table underneath shows median value and data range at each treatment condition.
Mentions: As expected, a dose-dependent cellular growth inhibition was observed with increasing concentrations of endoxifen treatment in YRI LCLs, with median percent viable cells decreased from 88% to 56% after 3 and 10 uM endoxifen 72 hours treatment. Moreover, the inter-individual variations appear to be larger at higher treatment concentrations, as shown in Figure 1.

Bottom Line: We identified 50 SNPs that associate with cellular sensitivity to endoxifen through their effects on 34 genes and 30 microRNA expression.Some of these findings are shared in both Caucasian and African samples, while others are unique in the African samples.Our integrative omic analysis facilitated the discovery of pharmacogenomic biomarkers that potentially affect tamoxifen sensitivity.

View Article: PubMed Central - PubMed

Affiliation: Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT
It has long been observed that tamoxifen sensitivity varies among breast cancer patients. Further, ethnic differences of tamoxifen therapy between Caucasian and African American have also been reported. Since most studies have been focused on Caucasian people, we sought to comprehensively evaluate genetic variants related to tamoxifen therapy in African-derived samples. An integrative "omic" approach developed by our group was used to investigate relationships among endoxifen (an active metabolite of tamoxifen) sensitivity, SNP genotype, mRNA and microRNA expressions in 58 HapMap YRI lymphoblastoid cell lines. We identified 50 SNPs that associate with cellular sensitivity to endoxifen through their effects on 34 genes and 30 microRNA expression. Some of these findings are shared in both Caucasian and African samples, while others are unique in the African samples. Among gene/microRNA that were identified in both ethnic groups, the expression of TRAF1 is also correlated with tamoxifen sensitivity in a collection of 44 breast cancer cell lines. Further, knock-down TRAF1 and over-expression of hsa-let-7i confirmed the roles of hsa-let-7i and TRAF1 in increasing tamoxifen sensitivity in the ZR-75-1 breast cancer cell line. Our integrative omic analysis facilitated the discovery of pharmacogenomic biomarkers that potentially affect tamoxifen sensitivity.

Show MeSH
Related in: MedlinePlus