title: Cytoplasmic Cyclin E Predicts Recurrence in Patients with Breast Cancer.
abstract: Purpose:Low molecular weight cyclin E (LMW-E) detected by Western blot analysis predicts for reduced breast cancer survival; however, it is impractical for clinical use. LMW-E lacks a nuclear localization signal that leads to accumulation in the cytoplasm that can be detected by IHC. We tested the hypothesis that cytoplasmic staining of cyclin E can be used as a predictor of poor outcome in different subtypes of breast cancer using patient cohorts with distinct clinical and pathologic features.Experimental Design:We evaluated the subcellular localization of cyclin E in breast cancer specimens from 2,494 patients from 4 different cohorts: 303 from a prospective study and 2,191 from retrospective cohorts [NCI, MD Anderson Cancer Center (MDA), and the United Kingdom (UK)]. Median follow-up times were 8.0, 10.1, 13.5, and 5.7 years, respectively.Results:Subcellular localization of cyclin E on IHC was associated with full-length (nuclear) and low molecular weight isoforms (cytoplasmic) of cyclin E on Western blot analysis. In multivariable analysis, cytoplasmic cyclin E staining was associated with the greatest risk of recurrence compared with other prognostic factors across all subtypes in three (NCI, MDA, and UK) of the cohorts. In the MDA cohort, cytoplasmic cyclin E staining outperformed Ki67 and all other variables as prognostic factors.Conclusions:Cytoplasmic cyclin E identifies patients with the highest likelihood of recurrence consistently across different patient cohorts and subtypes. These patients may benefit from alternative therapies targeting the oncogenic isoforms of cyclin E.Clin Cancer Res; 23(12); 2991-3002. ©2016 AACR.
authors.affiliation: Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Cansu
authors.initials: C
authors.lastname: Karakas
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Min Jin
authors.initials: MJ
authors.lastname: Ha
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Biernacka
authors.affiliation: Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yi
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Opoku
authors.initials: O
authors.lastname: Adjapong
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: Department of Pathology Administration, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bondy
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Thompson
authors.affiliation: School of Medicine, University of Nottingham, Nottingham, UK.
authors.forename: Kwok Leung
authors.initials: KL
authors.lastname: Cheung
authors.affiliation: School of Medicine, University of Nottingham, Nottingham, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Quintiles Transnational Corp, Denver, Colorado, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bacus
authors.affiliation: Department of Pathology Administration, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000302:isolation & purification; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D019927:Cyclin E / Q000235:genetics* / Q000302:isolation & purification; D003593:Cytoplasm / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D008970:Molecular Weight; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics* / Q000302:isolation & purification
chemical_list: D014408:Biomarkers, Tumor; D019927:Cyclin E; D020033:Protein Isoforms