title: The regulation and function of miR-21-FOXO3a-miR-34b/c signaling in breast cancer.
abstract: Upregulation of miR-21 (microRNA-21) and downregulation of miR-34b/c have been found in breast cancer (BC). However, their regulation mechanism and function roles in BC have not been fully addressed. Here, we report that miR-21 levels were inversely correlated with miR-34b/c levels in BC. MiR-21 upregulation contributes to PTEN downregulation, which is beneficial for the activation of PI3K/AKT signaling. The activation of AKT phosphorylates FOXO3a, triggering relocalization of FOXO3a proteins from the nucleus to the cytoplasm. FOXO3a is a newly identified transcription factor responsible for miR-34b/c expression. Downregulation of nuclear FOXO3a decreased the expression levels of miR-34b and miR-34c in breast cancer cells, in which p53 was mutated. We also found upregulation of circulating miR-21 and downregulation of circulating miR-34b/c in BC patients' serum. More importantly, we showed that systemic delivery of miR-34b/c or with anti-miR-21 significantly inhibited breast tumor growth in vivo. These results suggest that high circulating levels of miR-21 and low levels of miR-34b/c may provide potential biomarkers for BC diagnosis, and systemic delivery of miR-34b/c has potential as a therapeutic option for BC treatment.
authors: Department of General Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. lilitang474@yahoo.com.|Department of Breast Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. lilitang474@yahoo.com.
authors: Xiangyan
authors: X
authors: Liu
authors: Department of Nursing, Thomas Jefferson University, Philadelphia, PA 19107, USA. jie.feng@jefferson.edu.
authors: Jie
authors: J
authors: Feng
authors: Department of Breast Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. lilitang474@yahoo.com.
authors: Lili
authors: L
authors: Tang
authors: Department of General Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. musicjie302@yahoo.com.
authors: Liqiu
authors: L
authors: Liao
authors: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. qxwelcome@gmail.com.
authors: Qing
authors: Q
authors: Xu
authors: Department of General Surgery, the Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha 410013, China. zhushaihong@medmail.com.cn.
authors: Shaihong
authors: S
authors: Zhu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C524940:MIRN21 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
references: Nucleic Acids Res. 2009 May;37(8):2584-95
references: 19264808
references: Clin Cancer Res. 2009 Feb 1;15(3):752-7
references: 19188143
references: Cell Death Differ. 2010 Feb;17(2):193-9
references: 19461653
references: Cancer Res. 2010 Jul 15;70(14):5923-30
references: 20570894
references: Gynecol Oncol. 2010 Dec;119(3):586-93
references: 20801493
references: Cell Cycle. 2011 Feb 1;10(3):507-17
references: 21270527
references: Mol Cell. 2011 Feb 18;41(4):445-57
references: 21329882
references: Mol Ther. 2011 Jun;19(6):1116-22
references: 21427705
references: Clin Cancer Res. 2011 Jun 1;17(11):3600-18
references: 21505063
references: J Clin Invest. 2011 Sep;121(9):3442-55
references: 21841313
references: CA Cancer J Clin. 2013 Jan;63(1):11-30
references: 23335087
references: J Mol Cell Biol. 2013 Feb;5(1):3-13
references: 22935141
references: Oncogene. 2013 Sep 5;32(36):4294-303
references: 23001043
references: Clin Chem. 2013 Oct;59(10):1489-96
references: 23748853
references: Cell. 1999 Mar 19;96(6):857-68
references: 10102273
references: Cancer Res. 2005 Aug 15;65(16):7065-70
references: 16103053
references: Oncogene. 2005 Nov 14;24(50):7410-25
references: 16288288
references: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references: 16461460
references: Nature. 2007 Jun 28;447(7148):1130-4
references: 17554337
references: Curr Biol. 2007 Aug 7;17(15):1298-307
references: 17656095
references: Cancer Res. 2007 Dec 15;67(24):11612-20
references: 18089790
references: FEBS Lett. 2008 Apr 30;582(10):1564-8
references: 18406353
references: Oncogene. 2008 Jul 17;27(31):4373-9
references: 18372920
references: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6
references: 18755897
references: Cancer Res. 2008 Oct 1;68(19):8164-72
references: 18829576
references: Cancer Res. 2009 Oct 1;69(19):7569-76
references: 19773441