Estrogen coordinates translation and transcription, revealing a role for NRSF in human breast cancer cells.
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.
Bronson
Michael W
MW
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 70 Ship Street, Box G, Providence, Rhode Island 02903, USA.
Hillenmeyer
Sara
S
Park
Richard W
RW
Brodsky
Alexander S
AS
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
D004967:Estrogens; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
RNA. 2008 Jul;14(7):1337-51
18495938
Annu Rev Physiol. 2007;69:171-99
17037979
PLoS One. 2007 Feb 21;2(2):e242
17311107
PLoS Genet. 2007 Jun;3(6):e87
17542648
Mol Biosyst. 2009 Dec;5(12):1512-26
20023718
Cell. 2005 Jul 15;122(1):33-43
16009131
Mol Cell. 2007 Nov 9;28(3):501-12
17996713
Mol Endocrinol. 2007 Sep;21(9):2112-23
17550982
Cancer Cell. 2004 Jun;5(6):553-63
15193258
Nat Struct Biol. 2003 Dec;10(12):1039-47
14608375
Mol Cell. 2006 Aug 4;23(3):401-12
16885029
Bioinformatics. 2004 Jun 12;20(9):1464-5
14962934
Nature. 1990 Jun 7;345(6275):544-7
2348862
Mol Syst Biol. 2008;4:188
18414489
Curr Biol. 2005 Sep 6;15(17):R665-8
16139198
RNA. 2007 Jul;13(7):1116-31
17488873
Cancer Cell. 2006 Oct;10(4):331-42
17010674
Mol Endocrinol. 2005 Aug;19(8):1951-9
15705661
Cancer Res. 1987 Aug 15;47(16):4355-60
3607768
Cell Cycle. 2009 Jun 1;8(11):1675-80
19448403
Ann Surg. 2005 Oct;242(4):584-90; discussion 590-2
16192819
Nature. 1986 Mar 13-19;320(6058):134-9
3754034
Mol Endocrinol. 2005 Jun;19(6):1543-54
15802375
Cell. 2005 Jun 17;121(6):837-48
15960972
Nucleic Acids Res. 2009 May;37(8):2584-95
19264808
Neoplasia. 2007 Feb;9(2):166-80
17356713
Mol Cell. 2007 Apr 13;26(1):145-55
17434133
Science. 1986 Mar 7;231(4742):1150-4
3753802
Cancer Cell. 2008 May;13(5):381-3
18455121
Nat Genet. 2006 Nov;38(11):1289-97
17013392
Genome Biol. 2007;8(8):R159
17683528
Eur J Cancer. 2008 Dec;44(18):2753-9
19022662
Curr Opin Cell Biol. 1998 Apr;10(2):268-75
9561852
Nucleic Acids Res. 1989 Nov 25;17(22):9003-14
2587251
Oncogene. 2006 Oct 16;25(48):6423-35
17041627
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4408-13
19246391
J Biol Chem. 1988 Sep 5;263(25):12705-8
3045126
Nucleic Acids Res. 2009 Aug;37(14):4850-61
19528081
Mol Cell. 2003 Oct;12(4):889-901
14580340
Cancer Res. 2005 Jan 15;65(2):596-604
15695404
Cancer Sci. 2006 Nov;97(11):1198-204
16925584
Eur J Biochem. 1978 Sep 15;90(1):51-8
710420
Nucleic Acids Res. 2008 Jan;36(Database issue):D773-9
18086701
Endocrinology. 2004 Jul;145(7):3473-86
15033914
Proc Natl Acad Sci U S A. 1961 Feb 15;47:164-9
13773494
Cancer Res. 2004 Feb 15;64(4):1522-33
14973112
Nucleic Acids Res. 2005 Apr 28;33(8):2421-32
15860778
J Biol Chem. 2008 Jan 4;283(1):110-119
17984088
Cell Stem Cell. 2008 May 8;2(5):448-60
18462695
Cell. 2009 Feb 20;136(4):688-700
19239889
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
16199517
J Biol Chem. 2006 Sep 29;281(39):29011-21
16849329
Cancer Res. 2006 Jul 15;66(14):7334-40
16849584
Mol Cell. 2004 May 21;14(4):435-45
15149593
Ann Oncol. 2007 Aug;18(8):1323-8
17693645
J Biol Chem. 1997 May 9;272(19):12249-52
9139664
Genome Biol. 2005;6(13):R111
16420678
J Steroid Biochem Mol Biol. 1998 Aug;66(3):113-20
9719445
Oncogene. 2008 Feb 28;27(10):1472-7
17767197
Proc Natl Acad Sci U S A. 1963 Mar 15;49:373-9
13960756
Genome Biol. 2009;10(9):R90
19723326
Steroids. 2008 Oct;73(9-10):953-60
18249430
RNA. 2009 Oct;15(10):1917-28
19703940
Anticancer Res. 2000 May-Jun;20(3A):1343-51
10928042
EMBO J. 2006 Mar 8;25(5):1114-25
16467844
Nat Rev Genet. 2008 Jan;9(1):38-48
18071322
Mol Cell Biol. 2009 Jun;29(12):3413-23
19364822
Radiother Oncol. 2005 Aug;76(2):177-86
16098621
J Cell Biochem. 2008 Oct 15;105(3):670-7
18773413
Cancer Res. 2006 Oct 1;66(19):9461-6
17018601
Cell Cycle. 2006 Sep;5(17):1929-35
16929174
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6570-5
15100410
Nucl Recept Signal. 2006;4:e016
16862222
Brief Funct Genomic Proteomic. 2004 Aug;3(2):103-11
15355593
Oncogene. 2004 Apr 19;23(18):3189-99
15094768