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

Oncogene. 2010 Sep 9;29(36):5103-12. doi: 10.1038/onc.2010.253. Epub 2010 Jun 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Centrosome / metabolism*
  • Centrosome / pathology
  • Cyclin D1 / metabolism
  • Cyclin D1 / physiology*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 4 / physiology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Fibrocystic Breast Disease / genetics
  • Fibrocystic Breast Disease / metabolism
  • Genes, ras / genetics
  • Genes, ras / physiology*
  • Humans
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology
  • Mice
  • Mice, Transgenic
  • NIMA-Related Kinases
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Cyclin D1
  • NEK2 protein, human
  • NIMA-Related Kinases
  • Protein-Serine-Threonine Kinases
  • Cyclin-Dependent Kinase 4