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Differential recruitment of nuclear receptor coregulators in ligand-dependent transcriptional repression by estrogen receptor-α

Oncogene volume 30, pages 1608–1614 (2011)Cite this article

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Abstract

Estrogen receptors (ERs) are normally expressed in breast tissues and mediate hormonal functions during development and in female reproductive physiology. In the majority of breast cancers, ERs are involved in regulating tumor cell proliferation and serve as prognostic markers and therapeutic targets in the management of hormone-dependent tumors. At the molecular level, ERs function as ligand-dependent transcription factors and activate target-gene expression following hormone stimulation. Recent transcriptomic and whole-genome-binding studies suggest, however, that ligand-activated ERs can also repress the expression of a significant subset of target genes. To characterize the molecular mechanisms of transcriptional repression by ERs, we examined recruitment of nuclear receptor coregulators, histone modifications and RNA polymerase II docking at ER-binding sites and cis-regulatory regions adjacent to repressed target genes. Moreover, we utilized gene expression data from patient samples to determine potential roles of repressed target genes in breast cancer biology. Results from these studies indicate that nuclear receptor corepressor recruitment is a key feature of ligand-dependent transcriptional repression by Ers, and some repressed target genes are associated with disease progression and response to endocrine therapy. These findings provide preliminary insights into a novel aspect of the molecular mechanisms of ER functions and their potential roles in hormonal carcinogenesis and breast cancer biology.

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References

  • Ali S, Coombes RC . (2000). Estrogen receptor alpha in human breast cancer: occurrence and significance. J Mammary Gland Biol Neoplasia 5: 271–281.

    Article  CAS  PubMed  Google Scholar 

  • Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY et al. (1997). AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277: 965–968.

    Article  CAS  PubMed  Google Scholar 

  • Bookman MA . (2005). Is there still a role for hormonal therapy? Int J Gynecol Cancer 15 (Suppl 3): 291–297.

    Article  PubMed  Google Scholar 

  • Cappelletti V, Celio L, Bajetta E, Allevi A, Longarini R, Miodini P et al. (2004). Prospective evaluation of estrogen receptor-beta in predicting response to neoadjuvant antiestrogen therapy in elderly breast cancer patients. Endocr Relat Cancer 11: 761–770.

    Article  CAS  PubMed  Google Scholar 

  • Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ et al. (2005). Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122: 33–43.

    Article  CAS  PubMed  Google Scholar 

  • Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J et al. (2006). Genome-wide analysis of estrogen receptor binding sites. Nat Genet 38: 1289–1297.

    Article  CAS  PubMed  Google Scholar 

  • Cavailles V, Dauvois S, L′Horset F, Lopez G, Hoare S, Kushner PJ et al. (1995). Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. Embo J 14: 3741–3751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT et al. (1999). Regulation of transcription by a protein methyltransferase. Science 284: 2174–2177.

    Article  CAS  PubMed  Google Scholar 

  • Chen JD, Evans RM . (1995). A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377: 454–457.

    Article  CAS  PubMed  Google Scholar 

  • Fernandes I, Bastien Y, Wai T, Nygard K, Lin R, Cormier O et al. (2003). Ligand-dependent nuclear receptor corepressor LCoR functions by histone deacetylase-dependent and -independent mechanisms. Mol Cell 11: 139–150.

    Article  CAS  PubMed  Google Scholar 

  • Finlin BS, Gau CL, Murphy GA, Shao H, Kimel T, Seitz RS et al. (2001). RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer. J Biol Chem 276: 42259–42267.

    Article  CAS  PubMed  Google Scholar 

  • Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A et al. (2005). Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97: 1652–1662.

    Article  CAS  PubMed  Google Scholar 

  • Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM et al. (1998). Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371–1388.

    Article  CAS  PubMed  Google Scholar 

  • Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS . (2003). 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. Endocrinology 144: 4562–4574.

    Article  CAS  PubMed  Google Scholar 

  • Gruber CJ, Tschugguel W, Schneeberger C, Huber JC . (2002). Production and actions of estrogens. N Engl J Med 346: 340–352.

    Article  CAS  PubMed  Google Scholar 

  • Guenther MG, Barak O, Lazar MA . (2001). The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol 21: 6091–6101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown M . (1994). Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. Science 264: 1455–1458.

    Article  CAS  PubMed  Google Scholar 

  • Hebbes TR, Thorne AW, Crane-Robinson C . (1988). A direct link between core histone acetylation and transcriptionally active chromatin. Embo J 7: 1395–1402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu X, Lazar MA . (1999). The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402: 93–96.

    Article  CAS  PubMed  Google Scholar 

  • Lin CY, Strom A, Li Kong S, Kietz S, Thomsen JS, Tee JB et al (2007a). Inhibitory effects of estrogen receptor beta on specific hormone-responsive gene expression and association with disease outcome in primary breast cancer. Breast Cancer Res 9: R25.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin CY, Strom A, Vega VB, Kong SL, Yeo AL, Thomsen JS et al (2004). Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells. Genome Biol 5: R66.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin CY, Vega VB, Thomsen JS, Zhang T, Kong SL, Xie M et al (2007b). Whole-genome cartography of estrogen receptor alpha binding sites. PLoS Genet 3: e87.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin WJ, Gary JD, Yang MC, Clarke S, Herschman HR . (1996). The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J Biol Chem 271: 15034–15044.

    Article  CAS  PubMed  Google Scholar 

  • Lindberg MK, Moverare S, Skrtic S, Gao H, Dahlman-Wright K, Gustafsson JA et al (2003). Estrogen Receptor (ER)-beta reduces ERalpha-regulated gene transcription, supporting a ‘Ying Yang’ relationship between ERalpha and ERbeta in Mice. Mol Endocrinol 17: 203–208.

    Article  CAS  PubMed  Google Scholar 

  • Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M et al. (2003). Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115: 751–763.

    Article  CAS  PubMed  Google Scholar 

  • Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A et al. (2005). An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102: 13550–13555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS . (1999). An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proc Natl Acad Sci USA 96: 6947–6952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nilsson S, Gustafsson JA . (2002). Estrogen receptor action. Crit Rev Eukaryot Gene Expr 12: 237–257.

    Article  CAS  PubMed  Google Scholar 

  • Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y . (1996). The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87: 953–959.

    Article  CAS  PubMed  Google Scholar 

  • Onate SA, Tsai SY, Tsai MJ, O'Malley BW . (1995). Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270: 1354–1357.

    Article  CAS  PubMed  Google Scholar 

  • Phelan ML, Sif S, Narlikar GJ, Kingston RE . (1999). Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol Cell 3: 247–253.

    Article  CAS  PubMed  Google Scholar 

  • Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M . (2000). Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103: 843–852.

    Article  CAS  PubMed  Google Scholar 

  • Sjogren S, Inganas M, Norberg T, Lindgren A, Nordgren H, Holmberg L et al. (1996). The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 88: 173–182.

    Article  CAS  PubMed  Google Scholar 

  • Soulez M, Parker MG . (2001). Identification of novel oestrogen receptor target genes in human ZR75-1 breast cancer cells by expression profiling. J Mol Endocrinol 27: 259–274.

    Article  CAS  PubMed  Google Scholar 

  • Sterner DE, Berger SL . (2000). Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 64: 435–459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stossi F, Likhite VS, Katzenellenbogen JA, Katzenellenbogen BS . (2006). Estrogen-occupied estrogen receptor represses cyclin G2 gene expression and recruits a repressor complex at the cyclin G2 promoter. J Biol Chem 281: 16272–16278.

    Article  CAS  PubMed  Google Scholar 

  • Stossi F, Madak-Erdogan Z, Katzenellenbogen BS . (2009). Estrogen receptor alpha represses transcription of early target genes via p300 and CtBP1. Mol Cell Biol 29: 1749–1759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson JA . (1998). A regulatory role for RIP140 in nuclear receptor activation. Mol Endocrinol 12: 864–881.

    Article  CAS  PubMed  Google Scholar 

  • Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN et al. (2006). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. Jama 295: 2727–2741.

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Huang ZQ, Xia L, Feng Q, Erdjument-Bromage H, Strahl BD et al. (2001). Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293: 853–857.

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Cote J, Xue Y, Zhou S, Khavari PA, Biggar SR et al. (1996). Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. Embo J 15: 5370–5382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Webb P, Anderson CM, Valentine C, Nguyen P, Marimuthu A, West BL et al. (2000). The nuclear receptor corepressor (N-CoR) contains three isoleucine motifs (I/LXXII) that serve as receptor interaction domains (IDs). Mol Endocrinol 14: 1976–1985.

    Article  CAS  PubMed  Google Scholar 

  • Wei LN, Hu X, Chandra D, Seto E, Farooqui M . (2000). Receptor-interacting protein 140 directly recruits histone deacetylases for gene silencing. J Biol Chem 275: 40782–40787.

    Article  CAS  PubMed  Google Scholar 

  • Yager JD, Davidson NE . (2006). Estrogen carcinogenesis in breast cancer. N Engl J Med 354: 270–282.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a Mentoring Environment Grant (CYL) from Brigham Young University, a research grant (CYL) from the Women's Research Institute, NIH award number R03CA143981 (CYL) and summer research fellowships (KWM, JDC, RLS, KEK and NRC) from the BYU Cancer Research Center.

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  1. C-Y Lin

    Present address: 2Current address: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.,

Authors and Affiliations

  1. Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA

    K W Merrell, J D Crofts, R L Smith, J H Sin, K E Kmetzsch, A Merrell, R O Miguel, N R Candelaria & C-Y Lin

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Merrell, K., Crofts, J., Smith, R. et al. Differential recruitment of nuclear receptor coregulators in ligand-dependent transcriptional repression by estrogen receptor-α. Oncogene 30, 1608–1614 (2011). https://doi.org/10.1038/onc.2010.528

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