Tumoral expression of drug and xenobiotic metabolizing enzymes in breast cancer patients of different ethnicities with implications to personalized medicine

Abstract

Drug and xenobiotic metabolizing enzymes (DXME) play important roles in drug responses and carcinogenesis. Recent studies have found that expression of DXME in cancer cells significantly affects drug clearance and the onset of drug resistance. In this study we compared the expression of DXME in breast tumor tissue samples from patients representing three ethnic groups: Caucasian Americans (CA), African Americans (AA), and Asian Americans (AS). We further combined DXME gene expression data with eQTL data from the GTEx project and with allele frequency data from the 1000 Genomes project to identify SNPs that may be associated with differential expression of DXME genes. We identified substantial differences among CA, AA, and AS populations in the expression of DXME genes and in activation of pathways involved in drug metabolism, including those involved in metabolizing chemotherapy drugs that are commonly used in the treatment of breast cancer. These data suggest that differential expression of DXME may associate with health disparities in breast cancer outcomes observed among these three ethnic groups. Our study suggests that development of personalized treatment strategies for breast cancer patients could be improved by considering both germline genotypes and tumor specific mutations and expression profiles related to DXME genes.

Figure 1

The expression of 42 drug and xenobiotics metabolizing enzymes across breast cancers for Caucasian American (CA), African American (AA), Asian American (AS), all BRCA cancer samples from the three races (Tumor), and all normal samples from the three races (Normal). The mean expressions of all tumor BRCA samples (Tumor) were used as a reference and relative mean expression values from other groups were plotted using a color scheme to show qualitative differences. The values represent fold changes of different groups vs. Tumor group. There are totally 42 DXME genes that display significant differential expression between at least two comparisons (Tables 1 and S2, fold change ≥ 2 and adjusted p-value ≤ 0.05).

Figure 2

Expression of CYP2D6 in Asian American (AS), African American (AA), and Caucasian American (CA) breast cancer tissues. Y-axis is log2 of normalized expression values (in reads per million). The p-value for AA vs. AS comparison is 0.075, and the p-value for CA vs. AA comparison is 1.27e-06. The reason that the latter has much smaller p-value is because the sample sizes of AA and CA are much larger than that of AS.

Figure 3

Differential gene expression in the tamoxifen metabolism pathway. (A) Asian American vs African American. Up or down regulation means increase or decrease of gene expression in Asian American BRCA patient tumor tissues. (B) Asian American vs Caucasian American. Up or down regulation means increase or decrease of gene expression in Asian American BRCA patient tumor tissues. (C) African American vs Caucasian American. Up or down regulation means increase or decrease of gene expression in African American BRCA patient tumor tissues. The pathway diagrams with differential gene expression were made using Pathview package, where pathway diagrams were originally obtained from KEGG database^–.

Figure 4

Differential gene expression in xenobiotics metabolism pathway between Asian American and Caucasian American. Up or down regulation means increase or decrease of gene expression in Asian American BRCA patient tumor tissues. The pathway diagram with differential gene expression was made using Pathview package, where pathway diagrams were originally obtained from KEGG database^–.