title: The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness.
abstract: The role of the Forkhead box class O (FoxO)3a transcription factor in breast cancer migration and invasion is controversial. Here we show that FoxO3a overexpression decreases motility, invasiveness, and anchorage-independent growth in estrogen receptor α-positive (ERα+) cancer cells while eliciting opposite effects in ERα-silenced cells and in ERα-negative (ERα-) cell lines, demonstrating that the nuclear receptor represents a crucial switch in FoxO3a control of breast cancer cell aggressiveness. In ERα+ cells, FoxO3a-mediated events were paralleled by a significant induction of Caveolin-1 (Cav1), an essential constituent of caveolae negatively associated to tumor invasion and metastasis. Cav1 induction occurs at the transcriptional level through FoxO3a binding to a Forkhead responsive core sequence located at position -305/-299 of the Cav1 promoter. 17β-estradiol (E2) strongly emphasized FoxO3a effects on cell migration and invasion, while ERα and Cav1 silencing were able to reverse them, demonstrating that both proteins are pivotal mediators of these FoxO3a controlled processes. In vivo, an immunohistochemical analysis on tissue sections from patients with ERα+ or ERα- invasive breast cancers or in situ ductal carcinoma showed that nuclear FoxO3a inversely (ERα+) or directly (ERα-) correlated with the invasive phenotype of breast tumors. In conclusion, FoxO3a role in breast cancer motility and invasion depends on ERα status, disclosing a novel aspect of the well-established FoxO3a/ERα interplay. Therefore FoxO3a might become a pursuable target to be suitably exploited in combination therapies either in ERα+ or ERα- breast tumors.
authors.affiliation: Department of Pharmacy and Health and Nutritional Sciences; University of Calabria; Arcavacata di Rende; Cosenza, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Sisci
authors.forename: Pamela
authors.initials: P
authors.lastname: Maris
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cesario
authors.forename: Wanda
authors.initials: W
authors.lastname: Anselmo
authors.forename: Roberta
authors.initials: R
authors.lastname: Coroniti
authors.forename: Giovanna Elvi
authors.initials: GE
authors.lastname: Trombino
authors.forename: Francesco
authors.initials: F
authors.lastname: Romeo
authors.forename: Aurora
authors.initials: A
authors.lastname: Ferraro
authors.forename: Marilena
authors.initials: M
authors.lastname: Lanzino
authors.forename: Saveria
authors.initials: S
authors.lastname: Aquila
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
authors.forename: Loredana
authors.initials: L
authors.lastname: Mauro
authors.forename: Catia
authors.initials: C
authors.lastname: Morelli
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D000368:Aged; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D004958:Estradiol
keywords: breast cancer; estrogen receptor; forkhead transcription factors; invasion; motility
references.citation: Acta Med Okayama. 2004 Aug;58(4):197-205
references.pmid: 15551757
references.citation: Cell. 2004 Apr 16;117(2):225-37
references.pmid: 15084260
references.citation: J Mol Endocrinol. 2008 Nov;41(5):263-75
references.pmid: 18772268
references.citation: Breast Cancer Res Treat. 2006 Feb;95(3):219-28
references.pmid: 16244790
references.citation: Oncogene. 2004 Oct 14;23(47):7893-7
references.pmid: 15334058
references.citation: Biochem J. 2005 Feb 1;385(Pt 3):795-802
references.pmid: 15458387
references.citation: Oncogene. 2005 Nov 14;24(50):7410-25
references.pmid: 16288288
references.citation: J Steroid Biochem Mol Biol. 1998 Apr;65(1-6):163-8
references.pmid: 9699869
references.citation: Br J Cancer. 2008 Jul 22;99(2):327-34
references.pmid: 18612310
references.citation: Breast Cancer Res Treat. 1991 Dec;20(1):43-52
references.pmid: 1813068
references.citation: Breast Cancer Res. 2008;10(1):R21
references.pmid: 18312651
references.citation: Crit Rev Oncol Hematol. 2004 Jul;51(1):55-67
references.pmid: 15207254
references.citation: Mol Endocrinol. 2002 Jan;16(1):100-15
references.pmid: 11773442
references.citation: Cancer Res. 2009 Nov 15;69(22):8594-602
references.pmid: 19887621
references.citation: Cell. 2007 Jan 26;128(2):309-23
references.pmid: 17254969
references.citation: PLoS One. 2012;7(3):e32590
references.pmid: 22412893
references.citation: Breast Cancer Res Treat. 2011 Aug;129(1):11-21
references.pmid: 21336599
references.citation: Curr Drug Targets. 2011 Aug;12(9):1284-90
references.pmid: 21443462
references.citation: Mol Cell Biol. 2010 Feb;30(3):857-70
references.pmid: 19933843
references.citation: EMBO J. 2007 Jan 24;26(2):380-90
references.pmid: 17183370
references.citation: Curr Cancer Drug Targets. 2008 Nov;8(7):597-610
references.pmid: 18991569
references.citation: Oncogene. 2002 Apr 4;21(15):2365-75
references.pmid: 11948420
references.citation: Cancer Res. 2006 Nov 15;66(22):10647-51
references.pmid: 17108100
references.citation: Nucleic Acids Res. 2010 Sep;38(16):5351-65
references.pmid: 20421209
references.citation: J Biol Chem. 2001 Sep 7;276(36):33554-60
references.pmid: 11435445
references.citation: Nat Genet. 2006 Nov;38(11):1289-97
references.pmid: 17013392
references.citation: Clin Cancer Res. 2007 Jan 1;13(1):90-101
references.pmid: 17200343
references.citation: J Biol Chem. 2001 Jul 27;276(30):27907-12
references.pmid: 11353774
references.citation: Mol Cell Biol. 2009 Sep;29(18):4906-17
references.pmid: 19564415
references.citation: Curr Pharm Des. 2007;13(7):705-17
references.pmid: 17346185
references.citation: J Biol Chem. 2005 Jan 21;280(3):1901-10
references.pmid: 15531587
references.citation: Cell. 2005 Jul 15;122(1):33-43
references.pmid: 16009131
references.citation: Cancer Res. 2007 Jun 15;67(12):5763-70
references.pmid: 17575143
references.citation: Biochem Biophys Res Commun. 2008 Nov 7;376(1):215-20
references.pmid: 18778685
references.citation: Epigenetics. 2011 Aug;6(8):979-86
references.pmid: 21725198
references.citation: Cancer Cell. 2002 Jul;2(1):81-91
references.pmid: 12150827
references.citation: Nat Cell Biol. 2008 Feb;10(2):138-48
references.pmid: 18204439
references.citation: Mol Cell Biol. 1998 Feb;18(2):967-77
references.pmid: 9447994
references.citation: J Biol Chem. 2004 Dec 3;279(49):51630-46
references.pmid: 15355971
references.citation: Cancer Res. 2008 Oct 15;68(20):8210-20
references.pmid: 18922892
references.citation: J Clin Invest. 2011 Oct;121(10):3789-96
references.pmid: 21965335
references.citation: Breast Cancer Res Treat. 2010 Nov;124(1):63-77
references.pmid: 20052536
references.citation: Cancer Res. 2000 Nov 1;60(21):5977-83
references.pmid: 11085516
references.citation: Nat Methods. 2007 Nov;4(11):895-901
references.pmid: 17971780