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Cyclin E amplification, over-expression, and relapse-free survival in HER-2-positive primary breast cancer

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Tumor Biology

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.

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Acknowledgments

Authors would like to thank Mrs. Sari Toivola and Mrs. Kristiina Salonoja for their excellent technical assistance.

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Authors and Affiliations

  1. Laboratory of Cancer Biology, BioMediTech, University of Tampere, FI-33014, Tampere, Finland

    Satu Luhtala, Synnöve Staff & Jorma Isola

  2. Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland

    Synnöve Staff

  3. Department of Oncology, Tampere University Hospital, Tampere, Finland

    Minna Tanner

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  1. Satu Luhtala
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  2. Synnöve Staff
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  3. Minna Tanner
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  4. Jorma Isola
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Correspondence to Jorma Isola.

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This study was approved by the local ethics committee (R07082).

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Luhtala, S., Staff, S., Tanner, M. et al. Cyclin E amplification, over-expression, and relapse-free survival in HER-2-positive primary breast cancer. Tumor Biol. 37, 9813–9823 (2016). https://doi.org/10.1007/s13277-016-4870-z

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  • DOI: https://doi.org/10.1007/s13277-016-4870-z

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