title: miR-221/222 control luminal breast cancer tumor progression by regulating different targets.
abstract: α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3'UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted "normal" breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dentelli
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Traversa
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Rosso
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Togliatto
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Olgasi
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchiò
authors.affiliation: Department of Molecular Biotechnology and Health Sciences; University of Torino; Torino, Italy; Center for Translational Genomics and Bioinformatics; San Raffaele Scientific Institute; Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Department of Molecular Biotechnology and Health Sciences; University of Torino; Torino, Italy; Center for Translational Genomics and Bioinformatics; San Raffaele Scientific Institute; Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lembo
authors.affiliation: Department of Experimental Oncology; Regina Elena National Cancer Institute; Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bon
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Annaratone
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.affiliation: Department of Experimental Oncology; Regina Elena National Cancer Institute; Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Falcioni
authors.affiliation: Department of Medical Sciences; University of Torino; Torino, Italy.
authors.forename: Maria Felice
authors.initials: MF
authors.lastname: Brizzi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D039663:Integrin beta4 / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008156:Luciferases; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D017931:DNA Primers; D039663:Integrin beta4; D019394:Ki-67 Antigen; D008156:Luciferases; D035683:MicroRNAs; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D025521:Tumor Suppressor Proteins; C525709:MIR221, human; C525710:MIR222, human; C494092:STAT5A protein, human; C000606462:ADAM17 protein, human
keywords: ADAM-17; STAT5A; breast cancers; miR-221/222; β4 integrin
references.citation: Mol Aspects Med. 2008 Oct;29(5):258-89
references.pmid: 18762209
references.citation: FASEB J. 2004 Aug;18(11):1249-51
references.pmid: 15180953
references.citation: Mol Carcinog. 1989;2(6):361-8
references.pmid: 2695104
references.citation: Breast Cancer Res Treat. 2004 Dec;88(3):263-72
references.pmid: 15609129
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references.pmid: 16461460
references.citation: PLoS One. 2012;7(7):e40531
references.pmid: 22792362
references.citation: Oncogene. 2003 Mar 20;22(11):1638-52
references.pmid: 12642867
references.citation: Crit Rev Oncog. 2012;17(1):69-95
references.pmid: 22471665
references.citation: Eur J Cancer. 2010 Jan;46(2):298-311
references.pmid: 19948396
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: Cancer Res. 2009 Jul 15;69(14):5978-86
references.pmid: 19567674
references.citation: Nat Rev Cancer. 2006 Nov;6(11):857-66
references.pmid: 17060945
references.citation: Int J Biochem Cell Biol. 2002 Jan;34(1):1-5
references.pmid: 11733179
references.citation: J Cell Biol. 2005 Mar 28;168(7):1099-108
references.pmid: 15795318
references.citation: Semin Cell Dev Biol. 2009 Apr;20(2):126-37
references.pmid: 19049889
references.citation: Clin Cancer Res. 2009 Feb 15;15(4):1140-4
references.pmid: 19228719
references.citation: Nat Rev Cancer. 2009 Aug;9(8):550-62
references.pmid: 19629070
references.citation: Breast. 2011 Oct;20 Suppl 3:S63-70
references.pmid: 22015296
references.citation: Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3280-7
references.pmid: 16740748
references.citation: J Cell Biol. 1998 Jul 13;142(1):271-84
references.pmid: 9660880
references.citation: Biol Open. 2012 Jul 15;1(7):658-66
references.pmid: 23213459
references.citation: Breast Cancer Res. 2009;11(5):R77
references.pmid: 19874578
references.citation: Blood. 2012 May 10;119(19):4486-98
references.pmid: 22451425
references.citation: Surg Oncol Clin N Am. 2001 Apr;10(2):313-28, viii-ix
references.pmid: 11382589
references.citation: J Cell Biol. 1992 May;117(3):671-8
references.pmid: 1533398
references.citation: Cell. 2013 Apr 25;153(3):654-65
references.pmid: 23622248
references.citation: Genome Med. 2011 Aug 31;3(8):56
references.pmid: 21888691
references.citation: J Natl Cancer Inst. 2011 Nov 16;103(22):1656-64
references.pmid: 21960707
references.citation: Hybridoma. 1990 Jun;9(3):243-55
references.pmid: 2365382
references.citation: Breast Cancer Res. 2007;9(1):203
references.pmid: 17319974
references.citation: Int J Cancer. 2004 Feb 20;108(5):665-71
references.pmid: 14696092
references.citation: Cell Cycle. 2011 Feb 1;10(3):507-17
references.pmid: 21270527
references.citation: J Biol Chem. 2008 Nov 7;283(45):31079-86
references.pmid: 18790736
references.citation: Diabetologia. 2011 Jul;54(7):1930
references.pmid: 21461636
references.citation: Nature. 2012 Oct 4;490(7418):61-70
references.pmid: 23000897
references.citation: Oncogene. 2011 Dec 15;30(50):4930-40
references.pmid: 21643009
references.citation: Ann Oncol. 2008 Jun;19(6):1075-81
references.pmid: 18238782
references.citation: Arch Pathol Lab Med. 2010 Jul;134(7):e48-72
references.pmid: 20586616
references.citation: Mol Biol Cell. 2002 Jun;13(6):2031-44
references.pmid: 12058067
references.citation: PLoS One. 2012;7(4):e33361
references.pmid: 22485142
references.citation: Cancer Res. 1990 Sep 15;50(18):6075-86
references.pmid: 1975513
references.citation: Clin Cancer Res. 2008 Feb 15;14(4):1050-8
references.pmid: 18281537
references.citation: Mol Cell Biol. 2013 Oct;33(19):3795-804
references.pmid: 23878399
references.citation: J Biol Chem. 2000 Apr 7;275(14):10604-10
references.pmid: 10744756
references.citation: Cell Cycle. 2013 Aug 1;12(15):2409-22
references.pmid: 23839042
references.citation: Cancer Cell. 2012 Dec 11;22(6):796-811
references.pmid: 23238015
references.citation: Oncogene. 2004 Mar 4;23(9):1681-92
references.pmid: 14755254
references.citation: Breast Cancer Res. 2011 Oct 12;13(5):220
references.pmid: 22018398
references.citation: Sci Signal. 2011 Aug 09;4(186):pt5
references.pmid: 21868360
references.citation: Curr Opin Cell Biol. 2012 Oct;24(5):645-51
references.pmid: 22898530
references.citation: Histopathology. 1991 Nov;19(5):403-10
references.pmid: 1757079
references.citation: Cancer Cell. 2006 Dec;10(6):515-27
references.pmid: 17157791
references.citation: J Oncol. 2009;2009:950201
references.pmid: 19639033
references.citation: Oncotarget. 2013 Feb;4(2):242-55
references.pmid: 23479461
references.citation: Annu Rev Med. 2009;60:167-79
references.pmid: 19630570
references.citation: Oncogene. 2010 Dec 16;29(50):6581-90
references.pmid: 20802515
references.citation: J Biol Chem. 2003 May 16;278(20):18617-27
references.pmid: 12621058
references.citation: J Cell Biol. 1997 Dec 29;139(7):1873-84
references.pmid: 9412479
references.citation: J Cell Biol. 1995 Apr;129(2):473-87
references.pmid: 7721947
references.citation: Nat Rev Cancer. 2001 Oct;1(1):46-54
references.pmid: 11900251
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2588-90
references.pmid: 10077553
references.citation: Mol Biol Cell. 2007 Nov;18(11):4210-21
references.pmid: 17699601
references.citation: Nat Rev Cancer. 2008 Dec;8(12):929-41
references.pmid: 19005493
references.citation: Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1562-8
references.pmid: 20489169
references.citation: Breast Cancer Res. 2009;11(4):R52
references.pmid: 19630967
references.citation: Tumour Biol. 2013 Jun;34(3):1361-70
references.pmid: 23529451