Identification of AGR3 as a potential biomarker though public genomic data analysis of triple-negative (TN) versus triple-positive (TP) breast cancer (BC).

Abstract

31 Background: TNBCs have an aggressive clinical phenotype with worse prognosis than TPBC. Here we sought to identify other genomic changes in patients with TN vs. TPBC, by mining TCGA breast cancer genomic data using the NextBio Clinical platform. Methods: Breast cancer patients with decreased (n=51) and increased (n=46) ER/PR/HER2 mRNA levels were selected with the molecular filter in NB Clinical. Top-ranked differentially expressed genes were identified then analyzed via NB Research, which comprises a library of individually curated publically available research and clinical grade genomic data. Results: Whole transcriptome analysis of TNBC and TPBC patients identified anterior gradient-3 (AGR3), a protein disulfide isomerase, as most downregulated (TNBC vs. TPBC, fold change = -178.2, p=2.7E-32). AGR3 mRNA was reduced in 94% of TNBC and increased in 96% of TPBC patients. AGR3 was hypomethylated in 50% of TPBC vs. 4% of TNBC patients, suggesting regulation by methylation. When the entire breast cancer cohort was stratified by AGR3 expression, underexpression was prevalent in younger patients (<50 yr, 39%) compared to those with overexpression (<50 yr, 23%). Further, 63% of AGR3 underexpressing patients had severe TP53 mutations vs. 19% with AGR3 overexpression. Breast cancer was most correlated to AGR3 in the NextBio Disease Atlas, with supporting data from 110 studies. AGR3 expression was decreased in ER- vs. ER+, PR- vs. PR+, HER2- vs. HER2+, and G3 vs. G1 tumors, and AGR3 promoter was hypermethylated in ER- vs. ER+, consistent with the TCGA results. Body Atlas showed strongest AGR3 expression in mucosa, fallopian tube, breast, and epithelial cells, in line with its proposed role in epithelial barrier function. Knockdown Atlas results showed TP53 mutation associated with reduced AGR3 mRNA, and the PharmacoAtlas showed positive regulation of AGR3 by estrogen analogues. Conclusions: Using the NextBio Clinical and Research platforms, we identified AGR3 as a marker of TNBC vs. TPBC that correlates with TP53 mutation status. AGR3 may provide an alternate route of TNBC treatment. Its potential in regulating epithelial barrier function may provide insights into the mechanism of disease progression.