CARM1 Is an Important Determinant of ERα-Dependent Breast Cancer Cell Differentiation and Proliferation in Breast Cancer Cells

Breast cancers with estrogen receptor alpha (ER alpha) expression are often more differentiated histologically than ER alpha-negative tumors, but the reasons for this difference are poorly understood. One possible explanation is that transcriptional cofactors associated with ER alpha determine the expression of genes which promote a more differentiated phenotype. In this study, we identify one such cofactor as coactivator-associated arginine methyltransferase 1 (CARM1), a unique coactivator of ER alpha that can simultaneously block cell proliferation and induce differentiation through global regulation of ER alpha-regulated genes. CARM1 was evidenced as an ER alpha coactivator in cell-based assays, gene expression microarrays, and mouse xenograft models. In human breast tumors, CARM1 expression positively correlated with ER alpha levels in ER-positive tumors but was inversely correlated with tumor grade. Our findings suggest that coexpression of CARM1 and ER alpha may provide a better biomarker of well-differentiated breast cancer. Furthermore, our findings define an important functional role of this histone arginine methyltransferase in reprogramming ER alpha-regulated cellular processes, implicating CARM1 as a putative epigenetic target in ER-positive breast cancers. Cancer Res; 71(6); 2118-28. (C) 2011 AACR.