title: Cyclin E amplification, over-expression, and relapse-free survival in HER-2-positive primary breast cancer.
abstract: Cyclin E is a well-characterized cell cycle regulator and an amplified oncogene in breast cancer. Over-expression of cyclin E has generally been associated with poor survival. Recent studies have shown an interaction between HER-2 (ERBB2) and cyclin E, but the exact mechanism is unknown. Interestingly, cyclin E over-expression has been associated with trastuzumab resistance. We studied cyclin E over-expression, CCNE1 amplification, and relapse-free survival in HER-2-positive primary breast cancers treated with and without trastuzumab therapy. Formalin-fixed paraffin-embedded tissue samples from 202 HER-2-positive breast carcinomas were studied. Expression levels of cyclin E and proliferation marker Ki-67 were determined using immunohistochemistry. Chromogenic in situ hybridization (CISH) with a gene-specific bacterial artificial chromosome (BAC) probe was used to analyze presence of CCNE1 amplification. Majority of HER-2-positive breast carcinomas exhibited nuclear staining for cyclin E protein. Cyclin E was highly expressed (≥50 % cells) in 37 % of cases. Incidence of CCNE1 amplification (≥6 gene copies/cell or clusters) was 8 %. Cyclin E amplification and over-expression were strongly associated with each other, grade, hormone receptors, and Ki-67. Neither high cyclin E expression nor CCNE1 amplification was associated with relapse-free survival (RFS) irrespective of short-term (9-week regimen) adjuvant trastuzumab therapy. These results confirm cyclin E and HER-2 gene co-amplification in a fraction of HER-2-positive breast cancers. Cyclin E is frequently over-expressed but appears to have limited value as a prognostic or predictive factor in HER-2-positive breast cancer regardless of trastuzumab therapy.
authors.affiliation: Laboratory of Cancer Biology, BioMediTech, University of Tampere, FI-33014, Tampere, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Luhtala
authors.affiliation: Laboratory of Cancer Biology, BioMediTech, University of Tampere, FI-33014, Tampere, Finland.|Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland.
authors.forename: Synnöve
authors.initials: S
authors.lastname: Staff
authors.affiliation: Department of Oncology, Tampere University Hospital, Tampere, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Tanner
authors.affiliation: Laboratory of Cancer Biology, BioMediTech, University of Tampere, FI-33014, Tampere, Finland. jorma.isola@uta.fi.
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000556:secondary; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000556:secondary; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000556:secondary; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008819:Mice, Nude; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D019927:Cyclin E; D015513:Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C475820:CCNE1 protein, human; C508053:ERBB2 protein, human
keywords: Breast cancer; CCNE1; Cyclin E; HER-2; Immunohistochemistry; Survival
references.citation: Mol Cancer Ther. 2004 Dec;3(12 ):1585-92
references.pmid: 15634652
references.citation: Oncol Rep. 2004 Nov;12(5):1143-50
references.pmid: 15492807
references.citation: J Surg Oncol. 2003 Aug;83(4):241-7
references.pmid: 12884237
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3761-6
references.pmid: 21321214
references.citation: J Pathol. 2003 Apr;199(4):424-31
references.pmid: 12635132
references.citation: Semin Cell Dev Biol. 2005 Jun;16(3):311-21
references.pmid: 15840440
references.citation: Sci Transl Med. 2010 Jun 30;2(38):38ra47
references.pmid: 20592421
references.citation: Cancer. 2013 Mar 15;119(6):1140-8
references.pmid: 23065954
references.citation: Mod Pathol. 2010 Jul;23(7):1029-39
references.pmid: 20473280
references.citation: Oncogene. 1995 Sep 7;11(5):941-50
references.pmid: 7675453
references.citation: Am J Surg Pathol. 2009 May;33(5):759-67
references.pmid: 19252432
references.citation: N Engl J Med. 2002 Nov 14;347(20):1566-75
references.pmid: 12432043
references.citation: Breast Cancer Res. 2010;12(4):R56
references.pmid: 20663194
references.citation: Science. 1987 Jan 9;235(4785):177-82
references.pmid: 3798106
references.citation: Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1112-6
references.pmid: 8430082
references.citation: Cancer Invest. 2006 Oct;24(6):581-7
references.pmid: 16982462
references.citation: BMJ. 2010 Aug 11;341:c3620
references.pmid: 20702548
references.citation: Int Surg. 2011 Jul-Sep;96(3):245-53
references.pmid: 22216704
references.citation: Mol Cell Biol. 1995 Jul;15(7):3463-9
references.pmid: 7791752
references.citation: Mod Pathol. 2001 Oct;14(10):1036-42
references.pmid: 11598175
references.citation: Cancer Res. 2009 Apr 1;69(7):2817-25
references.pmid: 19318554
references.citation: Mol Cell Biol. 2001 Sep;21(18):6254-69
references.pmid: 11509668
references.citation: Hum Pathol. 2001 Jan;32(1):89-94
references.pmid: 11172300
references.citation: J Pathol. 2005 Feb;205(3):388-96
references.pmid: 15682439
references.citation: Oncogene. 2002 Sep 26;21(43):6573-86
references.pmid: 12242655
references.citation: Int J Cancer. 2001 Jul 15;93(2):283-7
references.pmid: 11410878
references.citation: Breast Cancer Res. 2009;11(3):R37
references.pmid: 19538720
references.citation: Mol Cell Biol. 1995 May;15(5):2612-24
references.pmid: 7739542
references.citation: Cancer Res. 2010 Jun 15;70(12):5074-84
references.pmid: 20530685
references.citation: Oncogene. 2010 Jul 8;29(27):3896-907
references.pmid: 20453888
references.citation: Breast Cancer Res. 2012 Oct 01;14(5):R129
references.pmid: 23025714
references.citation: Jpn J Clin Oncol. 2006 Mar;36(3):142-9
references.pmid: 16520356
references.citation: Front Oncol. 2012 Jun 18;2:62
references.pmid: 22720269
references.citation: Ann Surg Oncol. 2012 Mar;19(3):935-40
references.pmid: 21879270
references.citation: Breast Cancer Res. 2012 Mar 20;14(2):R53
references.pmid: 22433433
references.citation: Carcinogenesis. 2004 Mar;25(3):375-80
references.pmid: 14633656
references.citation: J Exp Clin Cancer Res. 2006 Mar;25(1):59-64
references.pmid: 16761619
references.citation: Cell Cycle. 2009 Apr 1;8(7):1062-8
references.pmid: 19305161
references.citation: Clin Breast Cancer. 2011 Apr;11(2):93-102
references.pmid: 21569995
references.citation: BMC Cancer. 2010 Oct 08;10:539
references.pmid: 20932292
references.citation: Br J Cancer. 1997;76(10):1288-92
references.pmid: 9374373
references.citation: Med Sci Monit. 2009 Feb;15(2):MT34-40
references.pmid: 19179977
references.citation: World J Surg Oncol. 2011 Mar 16;9:31
references.pmid: 21410943
references.citation: Tumour Biol. 2013 Dec;34(6):3423-30
references.pmid: 23775012
references.citation: Cancer Res. 2005 Nov 1;65(21):9727-34
references.pmid: 16266993
references.citation: Eur J Surg Oncol. 2001 Aug;27(5):464-71
references.pmid: 11504517
references.citation: BMC Res Notes. 2009 Jul 17;2:140
references.pmid: 19615042
references.citation: Cancer Res. 2000 Jan 15;60(2):481-9
references.pmid: 10667604
references.citation: Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3319-28
references.pmid: 16740753
references.citation: N Engl J Med. 2006 Feb 23;354(8):809-20
references.pmid: 16495393