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

Authors
  • Zeng, X
  • Shaikh, F Y
  • Harrison, M K
  • Adon, A M
  • Trimboli, A J
  • Carroll, K A
  • Sharma, N
  • Timmers, C
  • Chodosh, L A
  • Leone, G
  • Saavedra, H I
Type
Published Article
Journal
Oncogene
Publisher
Springer Nature
Publication Date
Sep 09, 2010
Volume
29
Issue
36
Pages
5103–5112
Identifiers
DOI: 10.1038/onc.2010.253
PMID: 20581865
Source
Medline
License
Unknown

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-Ras(G12D) and c-Myc were induced in mouse mammary glands. Although CA was observed in mammary tumors initiated by c-Myc or K-Ras(G12D), it was detected only in premalignant mammary lesions expressing K-Ras(G12D). 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-Ras(G12V) 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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