Abstract Cadmium (Cd) is a chemical pollutant of the natural and occupational environment and is reported to be associated with human carcinogenesis. The molecular mechanisms associated with Cd-induced prostate cancer remain elusive. This study provides evidence that Erk/MAPK signaling is a carcinogenic molecular fingerprint for Cd induced prostate cancer. Cd exposed RWPE1 (Cd-RWPE1) cells robustly formed tumors in nude mice. Functionally, chronic Cd exposure of RWPE1 cells promoted cell survival, proliferation and colony formation with inhibition of apoptosis. RT2 PCR array analysis of 84 genes involved in the Erk/MAPK pathway revealed induction of gene expression in Cd-RWPE1 cells compared to RWPE1. This was confirmed by individual TaqMan gene expression analysis. Gene Set Enrichment Analysis (GSEA) for differentially expressed genes in Cd-RWPE1 showed an enrichment of the Erk/MAPK pathway along with other pathways such as KEGG-ERBB, KEGG-Cell Cycle, KEGG-VEGF, KEGG-Pathways in cancer and KEGG-prostate cancer pathway. We randomly selected upregulated genes from the Erk/MAPK pathway and performed profile analysis in a prostate adenocarcinoma data set (n=534) from the TCGA/GDC data base. We observed upregulation of these genes in prostate cancer compared to normal prostate samples. Taken together, these data reveal that Erk/MAPK signaling is a major pathway involved in Cd-induced malignant transformation of normal prostate epithelial cells. Understanding the dominant oncogenic pathways involved in the malignant transformation of normal prostate epithelial cells may help develop optimal therapeutic strategies for prostate cancer. Citation Format: Pritha Dasgupta, Priyanka Kulkarni, Nadeem S. Bhat, Ravi Gupta, Yutaka Hashimoto, Sharanjot Saini, Altaf A. Dar, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Marisa Shiina, Rajvir Dahiya, Shahana Majid. Cadmium induced malignant transformation involves activation of the Erk/MAPK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4659.