Genetic alterations are associated with breast cancer, but do not provide an encompassing explanation for breast cancer etiology and progression. In this context, evidence has indicated aberrant epigenetic signalling is an important driver of carcinogenesis. Protein arginine methylation is a common post-translational epigenetic modification catalysed by a family of nine human protein arginine methyltransferases (PRMTs) that have critical roles in steroid/nuclear hormone receptor (NR) dependent breast cancers. We have demonstrated that PRMT6 is an NR coregulator necessary for optimal ER-dependent gene expression and proliferation. Moreover, we have shown that PRMT6 regulates the expression and alternative splicing of genes that regulate proliferation, tumour suppression and carcinogenesis. Our new preliminary data utilising human cohort cancer datasets demonstrates increased PRMT6 expression is associated with higher hazard ratio, and decreased probability of relapse free survival and overall survival in human breast cancer and several other cancer cohorts. RNA-seq analysis after gain and loss of function analysis in a mammary specific PRMT6 transgenic mouse model and PRMT6 depleted human breast cancer lines, respectively, demonstrated: (i) PRMT6 expression promotes carcinogenic pathways, in contrast PRMT6 knockdown is associated with the attenuation of tumourigenic processes in breast cancer, and (ii) pathway analysis indicated PRMT6 dependent gene expression was also involved in cell cycle signalling, and mesenchymal transitions. Moreover, we identified direct molecular crosstalk between E2/ER signalling and PRMT6 expression by ChIP-seq, ChIP-qPCR and expression analysis. Furthermore, PRMT6 expression regulates the transcription and expression of the a tumour suppressor, Phosphatase and Tensin Homolog (PTEN) gene. Finally, we identified PRMT6 dependent enrichment of drug-dependent gene signatures (associated with breast cancer treatment) and that aberrant epigenetic PRMT6 signalling is associated with drug resistance.