title: CDK11p58 inhibits ERα-positive breast cancer invasion by targeting integrin β3 via the repression of ERα signaling.
abstract: BACKGROUND
  CDK11(p58), a Ser/Thr kinase that belongs to the cell division cycle 2-like 1 (CDC2L1) subfamily, is associated with cell cycle progression, tumorigenesis and apoptotic signaling. CDK11(p58) is also involved in the regulation of steroid receptors, such as androgen and estrogen receptors. We previously found that CDK11(p58) was abnormally expressed in prostate cancer. However, its role in breast cancer remains unclear.
  
  
  METHODS
  CDK11(p58) expression was evaluated by immunohistochemical staining in a tissue array. A Transwell assay was used to detect invasion and metastasis in breast cancer cells. The TaqMan® Metastasis Gene Expression Assay was used to search for potential downstream factors in the CDK11(p58) signaling pathway. qRT-PCR was used to evaluate mRNA levels, and the dual luciferase array was used to analyze promoter activity. Western blotting was used to detect the protein level.
  
  
  RESULTS
  CDK11(p58) expression was negatively correlated with node status (P = 0.012), relapse status (P = 0.002) and metastasis status (P = 0.023). Kaplan-Meier survival curves indicated that the disease-free survival (DFS) was significantly poor in breast cancer patients with low CDK11 expression. Interestingly, using the breast cancer cell lines ZR-75-30 and MDA-MB-231, we found that CDK11(p58) was capable of repressing the migration and invasion of ERα-positive breast cancer cells, but not ERα-negative breast cancer cells, in a kinase-dependent manner. Gene expression assays demonstrated that integrin β3 mRNA was dramatically repressed by CDK11(p58), and luciferase results confirmed that the integrin β3 promoter was inhibited by CDK11(p58) through ERα repression. The expression of integrin β3 was highly related to ERα signaling; ERα overexpression stimulated integrin β3 expression, whereas siRNA-mediated knockdown of ERα attenuated integrin β3 expression.
  
  
  CONCLUSIONS
  These data indicate that CDK11(p58) is an anti-metastatic gene in ERα-positive breast cancer and that the regulation of integrin β3 by CDK11(p58) via the repression of ERα signaling may constitute part of a signaling pathway underlying breast cancer invasion.
authors.forename: Yayun
authors.initials: Y
authors.lastname: Chi
authors.forename: Sheng
authors.initials: S
authors.lastname: Huang
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Ruoji
authors.initials: R
authors.lastname: Zhou
authors.forename: Lisha
authors.initials: L
authors.lastname: Wang
authors.forename: Xiuying
authors.initials: X
authors.lastname: Xiao
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Breast Cancer Institute; Department of Breast Surgery, Fudan University Shanghai Cancer Center, Building 7, No, 270 Dong An Road, Shanghai 200032, China. wujiong1122@vip.sina.com.
authors.forename: Jiong
authors.initials: J
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D056743:Cyclin D3 / Q000235:genetics* / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: C534696:CCND3 protein, human; D056743:Cyclin D3; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C061248:ITGB3 protein, human; D039661:Integrin beta3
references.citation: Breast Cancer Res Treat. 2011 Jan;125(1):221-8
references.pmid: 20508983
references.citation: Breast Cancer Res. 2007;9(4):R48
references.pmid: 17662154
references.citation: Cell. 1995 Dec 15;83(6):835-9
references.pmid: 8521507
references.citation: Mol Endocrinol. 2010 Nov;24(11):2114-25
references.pmid: 20880986
references.citation: Mol Cell Proteomics. 2011 Oct;10(10):M110.005397
references.pmid: 21622897
references.citation: Nat Cell Biol. 2009 Nov;11(11):1275-6
references.pmid: 19884882
references.citation: Mol Cell Biol. 2007 Oct;27(20):7125-42
references.pmid: 17698582
references.citation: Chem Rev. 2001 Aug;101(8):2511-26
references.pmid: 11749386
references.citation: PLoS One. 2008 May 21;3(5):e2238
references.pmid: 18493596
references.citation: Intern Med J. 2004 May;34(5):266-9
references.pmid: 15151673
references.citation: N Engl J Med. 2006 Jan 19;354(3):270-82
references.pmid: 16421368
references.citation: Cancer Res. 2006 Mar 1;66(5):2716-24
references.pmid: 16510592
references.citation: FEBS Lett. 2006 Feb 6;580(3):813-21
references.pmid: 16413544
references.citation: J Biol Chem. 2011 Jan 21;286(3):1748-57
references.pmid: 21078675
references.citation: Genes Chromosomes Cancer. 1992 Nov;5(4):311-20
references.pmid: 1283319
references.citation: Cell. 1995 Dec 15;83(6):851-7
references.pmid: 8521509
references.citation: Cancer Res. 2006 Aug 1;66(15):7540-7
references.pmid: 16885352
references.citation: Biochem Biophys Res Commun. 2005 Feb 11;327(2):628-36
references.pmid: 15629159
references.citation: Cancer Hallm. 2013 Mar;1(1):38-49
references.pmid: 24611128
references.citation: Breast Cancer Res Treat. 2010 Jun;121(3):639-49
references.pmid: 19876733
references.citation: EMBO Rep. 2006 Apr;7(4):418-24
references.pmid: 16462731
references.citation: Mol Cell Biol. 1995 Jan;15(1):1-11
references.pmid: 7528324
references.citation: Cancer. 1998 Jan 15;82(2):317-22
references.pmid: 9445188
references.citation: Cell. 2007 Feb 9;128(3):459-75
references.pmid: 17289567
references.citation: PLoS One. 2011 Jan 31;6(1):e14600
references.pmid: 21297952
references.citation: Biochem Biophys Res Commun. 2009 Aug 28;386(3):493-8
references.pmid: 19538938
references.citation: J Mammary Gland Biol Neoplasia. 2003 Oct;8(4):383-94
references.pmid: 14985635
references.citation: BMC Cancer. 2006 Apr 12;6:92
references.pmid: 16608533
references.citation: Br J Cancer. 1999 Mar;79(9-10):1468-74
references.pmid: 10188892
references.citation: Cancer Res. 1991 Apr 1;51(7):1817-22
references.pmid: 2004366
references.citation: Nat Med. 2009 Oct;15(10):1163-9
references.pmid: 19734908
references.citation: Cancer Res. 2014 Mar 1;74(5):1338-48
references.pmid: 24448237
references.citation: Nat Rev Cancer. 2002 Feb;2(2):91-100
references.pmid: 12635172
references.citation: J Mammary Gland Biol Neoplasia. 1999 Oct;4(4):367-76
references.pmid: 10705920
references.citation: J Biochem. 2009 Mar;145(3):331-43
references.pmid: 19122208
references.citation: J Clin Oncol. 2010 Aug 10;28(23):3770-8
references.pmid: 20625127
references.citation: Int J Cancer. 2003 Nov 10;107(3):346-52
references.pmid: 14506732
references.citation: Mol Cancer Res. 2010 Jul;8(7):1037-47
references.pmid: 20551150
references.citation: Genes Dev. 2008 Apr 1;22(7):884-93
references.pmid: 18334619
references.citation: Prog Nucleic Acid Res Mol Biol. 2004;77:263-88
references.pmid: 15196895