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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. Access through your institution Buy or subscribe This is a preview of subscription content,

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R-RAS2/TC21 GTPASE FOUND IN TUMORS Article Open access 07 December 2022 TARGETING TRIM37-DRIVEN CENTROSOME DYSFUNCTION IN 17Q23-AMPLIFIED BREAST CANCER Article 09 September 2020 THE NEK2

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protection against breast cancers by cyclin D1 ablation. _Nature_ 411: 1017–1021. Article  CAS  PubMed  Google Scholar  Download references 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-Ras__G12D_ 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. AUTHOR INFORMATION Author notes * F Y Shaikh and M K Harrison: These authors

contributed equally to this work. AUTHORS AND AFFILIATIONS * 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 * 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 * Department of Pathology and Laboratory Medicine, Atlanta, GA, USA K A Carroll * Department of Cancer Biology and Abramson Family Cancer Research

Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA L A Chodosh Authors * X Zeng View author publications You can also search for this author inPubMed Google

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search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to H I Saavedra. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest.

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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 Download citation * Received: 23 October 2009 * Revised: 22 April 2010 * Accepted: 20 May 2010 * Published: 28 June 2010 * Issue Date: 09 September 2010

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cyclin D1 * Cdk4 * Nek2