MicroRNA cluster 221-222 and estrogen receptor alpha interactions in breast cancer.
BACKGROUND
Several lines of evidence have suggested that estrogen receptor alpha (ERalpha)-negative breast tumors, which are highly aggressive and nonresponsive to hormonal therapy, arise from ERalpha-positive precursors through different molecular pathways. Because microRNAs (miRNAs) modulate gene expression, we hypothesized that they may have a role in ER-negative tumor formation.


METHODS
Gene expression profiles were used to highlight the global changes induced by miRNA modulation of ERalpha protein. miRNA transfection and luciferase assays enabled us to identify new targets of miRNA 206 (miR-206) and miRNA cluster 221-222 (miR-221-222). Northern blot, luciferase assays, estradiol treatment, and chromatin immunoprecipitation were performed to identify the miR-221-222 transcription unit and the mechanism implicated in its regulation.


RESULTS
Different global changes in gene expression were induced by overexpression of miR-221-222 and miR-206 in ER-positive cells. miR-221 and -222 increased proliferation of ERalpha-positive cells, whereas miR-206 had an inhibitory effect (mean absorbance units [AU]: miR-206: 500 AU, 95% confidence interval [CI]) = 480 to 520; miR-221: 850 AU, 95% CI = 810 to 873; miR-222: 879 AU, 95% CI = 850 to 893; P < .05). We identified hepatocyte growth factor receptor and forkhead box O3 as new targets of miR-206 and miR-221-222, respectively. We demonstrated that ERalpha negatively modulates miR-221 and -222 through the recruitment of transcriptional corepressor partners: nuclear receptor corepressor and silencing mediator of retinoic acid and thyroid hormone receptor.


CONCLUSIONS
These findings suggest that the negative regulatory loop involving miR-221-222 and ERalpha may confer proliferative advantage and migratory activity to breast cancer cells and promote the transition from ER-positive to ER-negative tumors.
Di Leva
Gianpiero
G
Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, 460 West, 12th Ave, Columbus, OH 43210, USA.
Gasparini
Pierluigi
P
Piovan
Claudia
C
Ngankeu
Apollinaire
A
Garofalo
Michela
M
Taccioli
Cristian
C
Iorio
Marilena V
MV
Li
Meng
M
Volinia
Stefano
S
Alder
Hansjuerg
H
Nakamura
Tatsuya
T
Nuovo
Gerard
G
Liu
Yunlong
Y
Nephew
Kenneth P
KP
Croce
Carlo M
CM
D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
D047628:Estrogen Receptor alpha; D035683:MicroRNAs; D012333:RNA, Messenger; C506487:ESR1 protein, human; C546087:MIRN206 microRNA, human; C525709:MIR221, human; C525710:MIR222, human
Oncol Rep. 1998 Sep-Oct;5(5):1013-24
9683803
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):264-9
20018759
J Biol Chem. 2008 Nov 7;283(45):31079-86
18790736
J Steroid Biochem Mol Biol. 2002 Feb;80(2):239-56
11897507
J Mammary Gland Biol Neoplasia. 2001 Apr;6(2):183-92
11501578
Oncogene. 2001 May 28;20(24):3110-5
11420727
Mol Endocrinol. 2008 Feb;22(2):388-402
18006642
Cancer Res. 2006 Apr 1;66(7):3903-11
16585219
Clin Cancer Res. 2009 Feb 1;15(3):752-7
19188143
J Mammary Gland Biol Neoplasia. 2004 Jan;9(1):55-66
15082918
J Biol Chem. 2006 Jun 16;281(24):16272-8
16608856
Genome Res. 2007 Oct;17(10):1537-45
17785539
Mol Cell. 2007 Sep 7;27(5):691-700
17803935
FEBS J. 2009 Jun;276(12):3269-76
19438724
Cancer Res. 2005 Aug 15;65(16):7065-70
16103053
J Biol Chem. 2008 Oct 31;283(44):29897-903
18708351
EMBO J. 2007 Aug 8;26(15):3699-708
17627278
Cancer Invest. 2004;22(4):588-603
15565817
Oncogene. 2008 Sep 25;27(43):5651-61
18521080
Oncogene. 2005 Nov 14;24(50):7410-25
16288288
Breast Cancer Res. 2004;6(6):240-5
15535853
Mol Endocrinol. 2002 Oct;16(10):2231-42
12351689
Nat Rev Cancer. 2006 Mar;6(3):184-92
16453012
Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10101-6
10963673
Lancet. 1985 Feb 16;1(8425):364-6
2857419
J Cell Biol. 2006 Aug 28;174(5):677-87
16923828
Oncogene. 2008 Oct 23;27(49):6322-33
18663362
Oncogene. 2008 Jun 19;27(27):3845-55
18246122
Clin Cancer Res. 2009 Feb 15;15(4):1126-32
19228717
Breast Cancer Res Treat. 2007 Jun;103(2):239-46
17004110
Cancer Res. 2008 Jul 1;68(13):5004-8
18593897
J Cell Biochem. 2008 Aug 15;104(6):2091-106
18393360
Oncogene. 1998 Mar;16(11):1391-7
9525738
Nature. 2004 Sep 16;431(7006):350-5
15372042
Mol Endocrinol. 2007 May;21(5):1132-47
17312270
Cancer Cell. 2009 Dec 8;16(6):498-509
19962668
J Immunol. 2002 May 15;168(10):5024-31
11994454
Nature. 2004 Nov 11;432(7014):235-40
15531877
Nat Rev Cancer. 2006 Nov;6(11):857-66
17060945
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12909-14
19567831
Mol Endocrinol. 2001 Aug;15(8):1344-59
11463858
Mol Endocrinol. 2009 Aug;23(8):1215-30
19423651
Oncogene. 1998 Jul 30;17(4):425-32
9696035