title: Estrogen coordinates translation and transcription, revealing a role for NRSF in human breast cancer cells.
abstract: Posttranscriptional regulation may enhance or inhibit estrogen transcriptional control to promote proliferation of breast cancer cells. To understand how transcriptome and translational responses coordinate to drive proliferation, we determined estrogen's global and specific effects on translation regulation by comparing the genome-wide profiles of total mRNA, polysome-associated mRNA, and monosome-associated mRNAs in MCF-7 cells after stimulation by 1 h of 10 nm 17beta-estradiol (E2). We observe three significant, novel findings. 1) E2 regulates several transcripts and pathways at the translation level. 2) We find that polysome analysis has higher sensitivity than total RNA in detecting E2-regulated transcripts as exemplified by observing stronger E2-induced enrichment of E2 expression signatures in polysomes more than in total RNA. This increased sensitivity allowed the identification of the repression of neural restrictive silencing factor targets in polysome-associated RNA but not total RNA. NRSF activity was required for E2 stimulation of the cell cycle. 3) We observe that the initial translation state is already high for E2 up-regulated transcripts before E2 treatment and vice versa for E2 down-regulated transcripts. This suggests that the translation state anticipates potential E2-induced transcriptome levels. Together, these data suggest that E2 stimulates breast cancer cells by regulating translation using multiple mechanisms. In sum, we show that polysome profiling of E2 regulation of breast cancer cells provides novel insights into hormone action and can identify novel factors critical for breast cancer cell growth.
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 70 Ship Street, Box G, Providence, Rhode Island 02903, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Bronson
authors.forename: Sara
authors.initials: S
authors.lastname: Hillenmeyer
authors.forename: Richard W
authors.initials: RW
authors.lastname: Park
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Brodsky
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011132:Polyribosomes / Q000187:drug effects / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D000099229:RE1-Silencing Transcription Factor
chemical_list: D004967:Estrogens; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
references.citation: RNA. 2008 Jul;14(7):1337-51
references.pmid: 18495938
references.citation: Annu Rev Physiol. 2007;69:171-99
references.pmid: 17037979
references.citation: PLoS One. 2007 Feb 21;2(2):e242
references.pmid: 17311107
references.citation: PLoS Genet. 2007 Jun;3(6):e87
references.pmid: 17542648
references.citation: Mol Biosyst. 2009 Dec;5(12):1512-26
references.pmid: 20023718
references.citation: Cell. 2005 Jul 15;122(1):33-43
references.pmid: 16009131
references.citation: Mol Cell. 2007 Nov 9;28(3):501-12
references.pmid: 17996713
references.citation: Mol Endocrinol. 2007 Sep;21(9):2112-23
references.pmid: 17550982
references.citation: Cancer Cell. 2004 Jun;5(6):553-63
references.pmid: 15193258
references.citation: Nat Struct Biol. 2003 Dec;10(12):1039-47
references.pmid: 14608375
references.citation: Mol Cell. 2006 Aug 4;23(3):401-12
references.pmid: 16885029
references.citation: Bioinformatics. 2004 Jun 12;20(9):1464-5
references.pmid: 14962934
references.citation: Nature. 1990 Jun 7;345(6275):544-7
references.pmid: 2348862
references.citation: Mol Syst Biol. 2008;4:188
references.pmid: 18414489
references.citation: Curr Biol. 2005 Sep 6;15(17):R665-8
references.pmid: 16139198
references.citation: RNA. 2007 Jul;13(7):1116-31
references.pmid: 17488873
references.citation: Cancer Cell. 2006 Oct;10(4):331-42
references.pmid: 17010674
references.citation: Mol Endocrinol. 2005 Aug;19(8):1951-9
references.pmid: 15705661
references.citation: Cancer Res. 1987 Aug 15;47(16):4355-60
references.pmid: 3607768
references.citation: Cell Cycle. 2009 Jun 1;8(11):1675-80
references.pmid: 19448403
references.citation: Ann Surg. 2005 Oct;242(4):584-90; discussion 590-2
references.pmid: 16192819
references.citation: Nature. 1986 Mar 13-19;320(6058):134-9
references.pmid: 3754034
references.citation: Mol Endocrinol. 2005 Jun;19(6):1543-54
references.pmid: 15802375
references.citation: Cell. 2005 Jun 17;121(6):837-48
references.pmid: 15960972
references.citation: Nucleic Acids Res. 2009 May;37(8):2584-95
references.pmid: 19264808
references.citation: Neoplasia. 2007 Feb;9(2):166-80
references.pmid: 17356713
references.citation: Mol Cell. 2007 Apr 13;26(1):145-55
references.pmid: 17434133
references.citation: Science. 1986 Mar 7;231(4742):1150-4
references.pmid: 3753802
references.citation: Cancer Cell. 2008 May;13(5):381-3
references.pmid: 18455121
references.citation: Nat Genet. 2006 Nov;38(11):1289-97
references.pmid: 17013392
references.citation: Genome Biol. 2007;8(8):R159
references.pmid: 17683528
references.citation: Eur J Cancer. 2008 Dec;44(18):2753-9
references.pmid: 19022662
references.citation: Curr Opin Cell Biol. 1998 Apr;10(2):268-75
references.pmid: 9561852
references.citation: Nucleic Acids Res. 1989 Nov 25;17(22):9003-14
references.pmid: 2587251
references.citation: Oncogene. 2006 Oct 16;25(48):6423-35
references.pmid: 17041627
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4408-13
references.pmid: 19246391
references.citation: J Biol Chem. 1988 Sep 5;263(25):12705-8
references.pmid: 3045126
references.citation: Nucleic Acids Res. 2009 Aug;37(14):4850-61
references.pmid: 19528081
references.citation: Mol Cell. 2003 Oct;12(4):889-901
references.pmid: 14580340
references.citation: Cancer Res. 2005 Jan 15;65(2):596-604
references.pmid: 15695404
references.citation: Cancer Sci. 2006 Nov;97(11):1198-204
references.pmid: 16925584
references.citation: Eur J Biochem. 1978 Sep 15;90(1):51-8
references.pmid: 710420
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D773-9
references.pmid: 18086701
references.citation: Endocrinology. 2004 Jul;145(7):3473-86
references.pmid: 15033914
references.citation: Proc Natl Acad Sci U S A. 1961 Feb 15;47:164-9
references.pmid: 13773494
references.citation: Cancer Res. 2004 Feb 15;64(4):1522-33
references.pmid: 14973112
references.citation: Nucleic Acids Res. 2005 Apr 28;33(8):2421-32
references.pmid: 15860778
references.citation: J Biol Chem. 2008 Jan 4;283(1):110-119
references.pmid: 17984088
references.citation: Cell Stem Cell. 2008 May 8;2(5):448-60
references.pmid: 18462695
references.citation: Cell. 2009 Feb 20;136(4):688-700
references.pmid: 19239889
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: J Biol Chem. 2006 Sep 29;281(39):29011-21
references.pmid: 16849329
references.citation: Cancer Res. 2006 Jul 15;66(14):7334-40
references.pmid: 16849584
references.citation: Mol Cell. 2004 May 21;14(4):435-45
references.pmid: 15149593
references.citation: Ann Oncol. 2007 Aug;18(8):1323-8
references.pmid: 17693645
references.citation: J Biol Chem. 1997 May 9;272(19):12249-52
references.pmid: 9139664
references.citation: Genome Biol. 2005;6(13):R111
references.pmid: 16420678
references.citation: J Steroid Biochem Mol Biol. 1998 Aug;66(3):113-20
references.pmid: 9719445
references.citation: Oncogene. 2008 Feb 28;27(10):1472-7
references.pmid: 17767197
references.citation: Proc Natl Acad Sci U S A. 1963 Mar 15;49:373-9
references.pmid: 13960756
references.citation: Genome Biol. 2009;10(9):R90
references.pmid: 19723326
references.citation: Steroids. 2008 Oct;73(9-10):953-60
references.pmid: 18249430
references.citation: RNA. 2009 Oct;15(10):1917-28
references.pmid: 19703940
references.citation: Anticancer Res. 2000 May-Jun;20(3A):1343-51
references.pmid: 10928042
references.citation: EMBO J. 2006 Mar 8;25(5):1114-25
references.pmid: 16467844
references.citation: Nat Rev Genet. 2008 Jan;9(1):38-48
references.pmid: 18071322
references.citation: Mol Cell Biol. 2009 Jun;29(12):3413-23
references.pmid: 19364822
references.citation: Radiother Oncol. 2005 Aug;76(2):177-86
references.pmid: 16098621
references.citation: J Cell Biochem. 2008 Oct 15;105(3):670-7
references.pmid: 18773413
references.citation: Cancer Res. 2006 Oct 1;66(19):9461-6
references.pmid: 17018601
references.citation: Cell Cycle. 2006 Sep;5(17):1929-35
references.pmid: 16929174
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6570-5
references.pmid: 15100410
references.citation: Nucl Recept Signal. 2006;4:e016
references.pmid: 16862222
references.citation: Brief Funct Genomic Proteomic. 2004 Aug;3(2):103-11
references.pmid: 15355593
references.citation: Oncogene. 2004 Apr 19;23(18):3189-99
references.pmid: 15094768