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Oncogene ; 29(36): 5103-12, 2010 Sep 09.
Article in English | MEDLINE | ID: mdl-20581865

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.


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