CARM1 is an important determinant of ERα-dependent breast cancer cell differentiation and proliferation in breast cancer cells.

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.

[1]  M. Kilgore,et al.  Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells , 2008, Molecular Cancer.

[2]  S. Badve,et al.  Oestrogen-receptor-positive breast cancer: towards bridging histopathological and molecular classifications , 2008, Journal of Clinical Pathology.

[3]  B. O’Malley,et al.  Signaling within a Coactivator Complex: Methylation of SRC-3/AIB1 Is a MolecularSwitch for Complex Disassembly , 2006, Molecular and Cellular Biology.

[4]  G. Stein,et al.  Control of cell cycle regulated histone genes during proliferation and differentiation. , 1996, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[5]  W. McGuire,et al.  The value of estrogen and progesterone receptors in the treatment of breast cancer , 1980, Cancer.

[6]  Antonin Bukovsky,et al.  Multifaceted Regulation of Cell Cycle Progression by Estrogen: Regulation of Cdk Inhibitors and Cdc25A Independent of Cyclin D1-Cdk4 Function , 2001, Molecular and Cellular Biology.

[7]  B. Spiegelman,et al.  Terminal differentiation of human breast cancer through PPAR gamma. , 1998, Molecular cell.

[8]  J. Carroll,et al.  Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. , 2003, Endocrine-related cancer.

[9]  C. Langford,et al.  CARM1 Is Required in Embryonic Stem Cells to Maintain Pluripotency and Resist Differentiation , 2009, Stem cells.

[10]  M. Bhasin,et al.  CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells , 2010, Development.

[11]  D. Aswad,et al.  Regulation of transcription by a protein methyltransferase. , 1999, Science.

[12]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. , 1999, Critical reviews in oncology/hematology.

[13]  Barry Komm,et al.  Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. , 2003, Endocrinology.

[14]  A. Iavarone,et al.  Distinct mechanisms of cell cycle arrest control the decision between differentiation and senescence in human neuroblastoma cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  B. O’Malley,et al.  Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation , 2009, Proceedings of the National Academy of Sciences.

[16]  V. Iyer,et al.  CARM1 promotes adipocyte differentiation by coactivating PPARγ , 2008, EMBO reports.

[17]  M. Al-Dhaheri,et al.  Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells , 2004, Breast Cancer Research.

[18]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. , 2002, Histopathology.

[19]  W D Dupont,et al.  Prognostic significance of estrogen receptor status in breast cancer in relation to tumor stage, axillary node metastasis, and histopathologic grading , 1984, Cancer.

[20]  M. Hu,et al.  Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Eckert,et al.  The epidermal keratinocyte as a model for the study of gene regulation and cell differentiation. , 1997, Physiological reviews.

[22]  P. Watson,et al.  Breast tissue banking: collection, handling, storage, and release of tissue for breast cancer research. , 2006, Methods in molecular medicine.

[23]  Morag Park,et al.  Genome-wide identification of direct target genes implicates estrogen-related receptor alpha as a determinant of breast cancer heterogeneity. , 2009, Cancer research.

[24]  Mathieu Lupien,et al.  CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. , 2008, Cancer research.

[25]  M. Wiznerowicz,et al.  Conditional Suppression of Cellular Genes: Lentivirus Vector-Mediated Drug-Inducible RNA Interference , 2003, Journal of Virology.

[26]  E. Leygue,et al.  Expression of oestrogen receptor-β in oestrogen receptor-α negative human breast tumours , 2006, British Journal of Cancer.

[27]  C. Nguyen,et al.  Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation. , 2004, Journal of molecular endocrinology.

[28]  Wei Xu.  Nuclear receptor coactivators: the key to unlock chromatin. , 2005, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[29]  W. McGuire,et al.  Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. , 1984, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  T. Kouzarides,et al.  Methylation at arginine 17 of histone H3 is linked to gene activation , 2002, EMBO reports.

[31]  E. Gelmann,et al.  Differentiation state and invasiveness of human breast cancer cell lines , 2004, Breast Cancer Research and Treatment.

[32]  W. McGuire,et al.  Estrogen receptor variants in clinical breast cancer. , 1991, Molecular endocrinology.

[33]  J. Yates,et al.  A methylation-mediator complex in hormone signaling. , 2004, Genes & development.

[34]  Shen-Liang Chen,et al.  The Coactivator-associated Arginine Methyltransferase Is Necessary for Muscle Differentiation , 2002, The Journal of Biological Chemistry.

[35]  Arul M Chinnaiyan,et al.  Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivo in tumor xenografts and human breast tumors , 2006, Genome Biology.

[36]  J. Côté,et al.  The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. , 2007, Molecular cell.

[37]  P. V. van Diest,et al.  Concerted overexpression of the genes encoding p21 and cyclin D1 is associated with growth inhibition and differentiation in various carcinomas. , 1999, Molecular pathology : MP.

[38]  S. Martino,et al.  Prediction of Node-Negative Breast Cancer Outcome by Histologic Grading and S-Phase Analysis by Flow Cytometry: An Eastern Cooperative Oncology Group Study (2192) , 2001, American journal of clinical oncology.

[39]  F. Stossi,et al.  Estrogen-occupied Estrogen Receptor Represses Cyclin G2 Gene Expression and Recruits a Repressor Complex at the Cyclin G2 Promoter* , 2006, Journal of Biological Chemistry.

[40]  Andrew Skildum,et al.  The Cyclin-dependent Kinase Inhibitor p21WAF1/Cip1 Is an Antiestrogen-regulated Inhibitor of Cdk4 in Human Breast Cancer Cells* , 2002, The Journal of Biological Chemistry.

[41]  C. Sardet,et al.  Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene , 2006, Proceedings of the National Academy of Sciences.

[42]  P. Watson,et al.  The NCIC-Manitoba Breast Tumor Bank: a resource for applied cancer research. , 1996, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[43]  C. Jung,et al.  Differential CARM1 expression in prostate and colorectal cancers , 2010, BMC Cancer.

[44]  Clifford A. Meyer,et al.  Coactivator Function Defines the Active Estrogen Receptor Alpha Cistrome , 2009, Molecular and Cellular Biology.

[45]  S. Richard,et al.  Loss of CARM1 Results in Hypomethylation of Thymocyte Cyclic AMP-regulated Phosphoprotein and Deregulated Early T Cell Development* , 2004, Journal of Biological Chemistry.

[46]  S. Karmakar,et al.  Unique roles of p160 coactivators for regulation of breast cancer cell proliferation and estrogen receptor-alpha transcriptional activity. , 2009, Endocrinology.

[47]  Z. Werb,et al.  GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. , 2008, Cancer cell.

[48]  S. Inoue,et al.  Estrogen receptors and their downstream targets in cancer. , 2004, Archives of histology and cytology.