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Cancer Therapy: Clinical

Cytoplasmic Cyclin E Predicts Recurrence in Patients with Breast Cancer

Kelly K. Hunt, Cansu Karakas, Min Jin Ha, Anna Biernacka, Min Yi, Aysegul A. Sahin, Opoku Adjapong, Gabriel N. Hortobagyi, Melissa L. Bondy, Patricia A. Thompson, Kwok Leung Cheung, Ian O. Ellis, Sarah Bacus, W. Fraser Symmans, Kim-Anh Do and Khandan Keyomarsi
Kelly K. Hunt
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: kkeyomar@mdanderson.orgkhunt@mdanderson.org
Cansu Karakas
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Min Jin Ha
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Anna Biernacka
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Min Yi
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Aysegul A. Sahin
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Opoku Adjapong
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Gabriel N. Hortobagyi
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Melissa L. Bondy
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
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Patricia A. Thompson
Department of Pathology, Stony Brook School of Medicine, Stony Brook, New York.
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Kwok Leung Cheung
School of Medicine, University of Nottingham, Nottingham, United Kingdom.
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Ian O. Ellis
School of Medicine, University of Nottingham, Nottingham, United Kingdom.
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Sarah Bacus
Quintiles Transnational Corp, Denver, Colorado.
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W. Fraser Symmans
Department of Pathology Administration, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Kim-Anh Do
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Khandan Keyomarsi
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: kkeyomar@mdanderson.orgkhunt@mdanderson.org
DOI: 10.1158/1078-0432.CCR-16-2217
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Abstract

Background: 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.

Methods: 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; 1–12. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received September 2, 2016.
  • Revision received November 7, 2016.
  • Accepted November 8, 2016.
  • ©2016 American Association for Cancer Research.
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Published OnlineFirst March 16, 2017
doi: 10.1158/1078-0432.CCR-16-2217

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Cytoplasmic Cyclin E Predicts Recurrence in Patients with Breast Cancer
Kelly K. Hunt, Cansu Karakas, Min Jin Ha, Anna Biernacka, Min Yi, Aysegul A. Sahin, Opoku Adjapong, Gabriel N. Hortobagyi, Melissa L. Bondy, Patricia A. Thompson, Kwok Leung Cheung, Ian O. Ellis, Sarah Bacus, W. Fraser Symmans, Kim-Anh Do and Khandan Keyomarsi
Clin Cancer Res March 16 2017 DOI: 10.1158/1078-0432.CCR-16-2217

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Cytoplasmic Cyclin E Predicts Recurrence in Patients with Breast Cancer
Kelly K. Hunt, Cansu Karakas, Min Jin Ha, Anna Biernacka, Min Yi, Aysegul A. Sahin, Opoku Adjapong, Gabriel N. Hortobagyi, Melissa L. Bondy, Patricia A. Thompson, Kwok Leung Cheung, Ian O. Ellis, Sarah Bacus, W. Fraser Symmans, Kim-Anh Do and Khandan Keyomarsi
Clin Cancer Res March 16 2017 DOI: 10.1158/1078-0432.CCR-16-2217
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Clinical Cancer Research
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