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Cyclin D1b protein expression in breast cancer is independent of cyclin D1a and associated with poor disease outcome

Oncogene volume 28, pages 1812–1820 (2009)Cite this article

Abstract

Aberrant expression of cyclin D1 protein is a common feature of breast cancer. However, the CCND1 gene encodes two gene products, cyclin D1a and cyclin D1b, which have discrete mechanisms of regulation and impact on cell behavior. A polymorphism at nucleotide 870 in the CCND1 gene, rs603965, influences the relative production of the encoded proteins and can impart increased risk for tumor development. Here, the impact of both the G/A870 polymorphism and cyclin D1b protein production on breast cancer risk, disease phenotype and patient outcome was analysed. In a large multiethnic case–control study, the G/A870 polymorphism conferred no significant risk for breast cancer overall or by stage or estrogen receptor (ER) status. However, the cyclin D1b protein was found to be upregulated in breast cancer, independent of cyclin D1a levels, and exhibited heterogeneous levels in breast cancer specimens. High cyclin D1a expression inversely correlated with the Ki67 proliferation marker and was not associated with clinical outcome. In contrast, elevated cyclin D1b expression was independently associated with adverse outcomes, including recurrence, distant metastasis and decreased survival. Interestingly, cyclin D1b was particularly associated with poor outcome in the context of ER-negative breast cancer. Thus, specific cyclin D1 isoforms are associated with discrete forms of breast cancer and high cyclin D1b protein levels hold prognostic potential.

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Acknowledgements

The authors thank all of the laboratory and administrative staff that contributed to the editing and preparation of the manuscript. This work was supported by the following grants: the National Health and Medical Research Council of Australia (Grant no. 276408), the Cancer Institute NSW, the Petre Foundation and the RT Hall Trust, the National Institutes of Health Grant CA104213 (ESK), the National Institutes of Health Grant CA099996 (KEK). We thank Drs Paul Crea and Davendra Segara of St Vincent's Clinic for access to patient material and data.

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Authors and Affiliations

  1. Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    E K A Millar, C M McNeil, S A O'Toole, S M Henshall, E A Musgrove & R L Sutherland

  2. Department of Anatomical Pathology South Eastern Area Laboratory Service, St George Hospital, Sydney, New South Wales, Australia

    E K A Millar

  3. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    J L Dean, T Tran, J Lin, A Quong, C E S Comstock, A Witkiewicz, H Rui, K E Knudsen & E S Knudsen

  4. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA

    J L Dean, T Tran, J Lin, C E S Comstock, A Witkiewicz, H Rui, K E Knudsen & E S Knudsen

  5. Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA

    A Witkiewicz

  6. Epidemiology Program, Cancer Research Center of Hawaii, Honolulu, HI, USA

    L LeMarchand

  7. Department of Preventive Medicine/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    V W Setiawan & C A Haiman

  8. Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA

    K E Knudsen

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Correspondence to E S Knudsen.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Millar, E., Dean, J., McNeil, C. et al. Cyclin D1b protein expression in breast cancer is independent of cyclin D1a and associated with poor disease outcome. Oncogene 28, 1812–1820 (2009). https://doi.org/10.1038/onc.2009.13

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