title: CARM1 is an important determinant of ERα-dependent breast cancer cell differentiation and proliferation in breast cancer cells.
abstract: Breast cancers with estrogen receptor α (ERα) expression are often more differentiated histologically than ERα-negative tumors, but the reasons for this difference are poorly understood. One possible explanation is that transcriptional cofactors associated with ERα 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 ERα that can simultaneously block cell proliferation and induce differentiation through global regulation of ERα-regulated genes. CARM1 was evidenced as an ERα coactivator in cell-based assays, gene expression microarrays, and mouse xenograft models. In human breast tumors, CARM1 expression positively correlated with ERα levels in ER-positive tumors but was inversely correlated with tumor grade. Our findings suggest that coexpression of CARM1 and ERα 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 ERα-regulated cellular processes, implicating CARM1 as a putative epigenetic target in ER-positive breast cancers.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706, USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Al-Dhaheri
authors.forename: Jiacai
authors.initials: J
authors.lastname: Wu
authors.forename: Georgios P
authors.initials: GP
authors.lastname: Skliris
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Ken
authors.initials: K
authors.lastname: Higashimato
authors.forename: Yidan
authors.initials: Y
authors.lastname: Wang
authors.forename: Kevin P
authors.initials: KP
authors.lastname: White
authors.forename: Paul
authors.initials: P
authors.lastname: Lambert
authors.forename: Yuerong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Leigh
authors.initials: L
authors.lastname: Murphy
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D047628:Estrogen Receptor alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004958:Estradiol; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1