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.
Highlights
Tamoxifen (TAM) is a selective estrogen receptor (ER) modulator that has been used to treat and prevent breast cancer for 30 years [1]
A dose-dependent cellular growth inhibition was observed with increasing concentrations of endoxifen treatment in YRI lymphoblastoid cell lines (LCLs), with median percent viable cells decreased from 88% to 56% after 3 and 10 uM endoxifen 72 hours treatment
In order to fill in the void of lack of study focusing in ethnic minority, we chose to quantitatively evaluate the cellular growth inhibition induced by endoxifen in HapMap YRI LCLs
Summary
Tamoxifen (TAM) is a selective estrogen receptor (ER) modulator that has been used to treat and prevent breast cancer for 30 years [1]. Patients taking TAM medication have exhibited a large variety of side effects, such as hot flashes and osteoporosis, which varied greatly from patient to patient [3]. All these highlight the need of conducting pharmacogenomic research to identify biomarkers so that patient’s responses to TAM therapy could be predicted and treatment outcomes could be improved. Ethnic differences were observed between Caucasianand African-derived populations both in breast cancer incidence and treatment outcomes. African American patients appeared to have lower incidence in ER-positive breast cancer than Caucasian Americans [5].These ethnic differences highlight the need to conduct pharmacogenomics research in African-derived population
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