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.
©2011 AACR.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Cycle
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Cell Differentiation*
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Cell Line, Tumor
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Cell Proliferation*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Estradiol / pharmacology
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism*
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Immunohistochemistry
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mice
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Mice, Nude
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Oligonucleotide Array Sequence Analysis
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Protein-Arginine N-Methyltransferases / genetics
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Protein-Arginine N-Methyltransferases / metabolism*
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Tissue Array Analysis
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Transplantation, Heterologous
Substances
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Cyclin-Dependent Kinase Inhibitor p21
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Estrogen Receptor alpha
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Cyclin-Dependent Kinase Inhibitor p27
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Estradiol
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Protein-Arginine N-Methyltransferases
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coactivator-associated arginine methyltransferase 1