Integrative "omic" analysis for tamoxifen sensitivity through cell based models.
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.
Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
Liming
L
Weng
Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
Dana
D
Ziliak
Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
Bonnie
B
Lacroix
Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
Paul
P
Geeleher
Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
R Stephanie
RS
Huang
D044383:Black People / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D001741:Black or African American
D035683:MicroRNAs; D012333:RNA, Messenger; D047990:TNF Receptor-Associated Factor 1; D013629:Tamoxifen