Protein arginine methyltransferases (PRMTs) methylate arginine residues on histones and target transcription factors that play critical roles in many cellular processes, including gene transcription, mRNA splicing, proliferation and differentiation. Recent studies have linked PRMT-dependent epigenetic marks and modifications to carcinogenesis and metastasis in cancer. However, the role of PRMT2-dependent signaling in breast cancer remains obscure. We demonstrate protein arginine methyltransferase-2 (PRMT2) mRNA expression was significantly decreased in breast cancer relative to normal breast. Gene expression profiling, Ingenuity and PPI network analysis after PRMT2-siRNA transfection into MCF-7 cells, revealed that PRMT2-dependent gene expression is involved in cell-cycle regulation and checkpoint control, chromosomal instability, DNA repair and carcinogenesis. For example, PRMT2 depletion: (i) increased p21 and decreased cyclinD1 expression in (several) breast cancer cell lines, (ii) decreased cell migration, (iii) induced an increase in nucleotide excision repair and homologous recombination DNA mismatch repair and (iv) increased the probability of distance metastasis free survival (DMFS). The expression of PRMT2 and retinoid-related orphan receptor gamma (RORγ) is inversely correlated in ER+ve breast cancer and increased RORγ expression increases DMFS. Furthermore, we found decreased expression of the PRMT2 dependent signature is significantly associated with increased probability of DMFS. Finally, weighted gene co-expression network analysis demonstrated a significant correlation between PRMT2-dependent genes, and cell-cycle checkpoint, kinetochore and DNA repair "circuits". Strikingly, these PRMT2-dependent "circuits" are correlated with pan-cancer metagene signatures associated with epithelial-mesenchymal transition (EMT) and chromosomal instability (CIN). This study demonstrates the role and significant correlation between a histone methyltransferase (PRMT2)-dependent signature, RORγ, the cell-cycle regulation, DNA repair "circuits", and breast cancer survival outcomes.