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The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2

Oncogene volume 29, pages 5103–5112 (2010)Cite this article

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Abstract

Centrosome amplification (CA) contributes to carcinogenesis by generating aneuploidy. Elevated frequencies of CA in most benign breast lesions and primary tumors suggest a causative role for CA in breast cancers. Clearly, identifying which and how altered signal transduction pathways contribute to CA is crucial to breast cancer control. Although a causative and cooperative role for c-Myc and Ras in mammary tumorigenesis is well documented, their ability to generate CA during mammary tumor initiation remains unexplored. To answer that question, K-RasG12D and c-Myc were induced in mouse mammary glands. Although CA was observed in mammary tumors initiated by c-Myc or K-RasG12D, it was detected only in premalignant mammary lesions expressing K-RasG12D. CA, both in vivo and in vitro, was associated with increased expression of the centrosome-regulatory proteins, cyclin D1 and Nek2. Abolishing the expression of cyclin D1, Cdk4 or Nek2 in MCF10A human mammary epithelial cells expressing H-RasG12V abrogated Ras-induced CA, whereas silencing cyclin E1 or B2 had no effect. Thus, we conclude that CA precedes mammary tumorigenesis, and interfering with centrosome-regulatory targets suppresses CA.

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Acknowledgements

We thank Drs Rene Opavsky, Paul W Doetsch, Ya Wang and Hui Wang for manuscript discussions. We also thank Ms Carla G Saavedra and Meredith Roberts for editing; Dr Harold Varmus for providing tetO-K-RasG12D mice; Dr J Brugge for nontransformed MCF10A cells; and Jana Opavska, Joi Carmichael and Stacy Sannem for technical assistance. We thank Dr Adam Marcus (from the Emory Imaging Core) and Mr Alan Bakaletz, for imaging advice. Lewis A Chodosh was funded by NIH R01CA98371, DOD BCRP W81XWH-05-1-0405 and NIH U01 CA105490, Gustavo Leone by R01CA85619, R01HD042619, R01CA121275, R01HD047470 and P01CA097189, Harold Saavedra by K01CA104079, and a Georgia Cancer Coalition Distinguished Scholar Award.

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  1. F Y Shaikh and M K Harrison: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Emory University School of Medicine, and Emory Winship Cancer Institute, Atlanta, GA, USA

    X Zeng, M K Harrison, A M Adon & H I Saavedra

  2. Department of Molecular Virology, Immunology and Medical Genetics, Program of Human Cancer Genetics, Columbus, OH, USA

    F Y Shaikh, A J Trimboli, N Sharma, C Timmers & G Leone

  3. Department of Pathology and Laboratory Medicine, Atlanta, GA, USA

    K A Carroll

  4. Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    L A Chodosh

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  1. X Zeng
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Zeng, X., Shaikh, F., Harrison, M. et al. The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2. Oncogene 29, 5103–5112 (2010). https://doi.org/10.1038/onc.2010.253

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