Weng Liming, Ziliak Dana, Lacroix Bonnie, Geeleher Paul, Huang R Stephanie
Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
PLoS One. 2014 Apr 3;9(4):e93420. doi: 10.1371/journal.pone.0093420. eCollection 2014.
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.
长期以来人们观察到，乳腺癌患者对他莫昔芬的敏感性存在差异。此外，也有报道称白种人和非裔美国人在他莫昔芬治疗方面存在种族差异。由于大多数研究都集中在白种人身上，我们试图全面评估非洲裔样本中与他莫昔芬治疗相关的基因变异。我们团队开发的一种综合“组学”方法用于研究58个HapMap YRI淋巴母细胞系中内昔芬（他莫昔芬的活性代谢物）敏感性、单核苷酸多态性（SNP）基因型、mRNA和微小RNA表达之间的关系。我们通过对34个基因和30个微小RNA表达的影响，鉴定出50个与细胞对内昔芬敏感性相关的SNP。其中一些发现白种人和非洲裔样本中都有，而其他一些则是非洲裔样本所特有的。在两个种族群体中都鉴定出的基因/微小RNA中，TRAF1的表达在44个乳腺癌细胞系中也与他莫昔芬敏感性相关。此外，敲低TRAF1和过表达hsa-let-7i证实了hsa-let-7i和TRAF1在增加ZR-75-1乳腺癌细胞系对他莫昔芬敏感性方面的作用。我们的综合组学分析有助于发现可能影响他莫昔芬敏感性的药物基因组生物标志物。
