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The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2. Oncogene 2010 Sep 09;29(36):5103-12

Date

06/29/2010

Pubmed ID

20581865

Pubmed Central ID

PMC2972189

DOI

10.1038/onc.2010.253

Scopus ID

2-s2.0-77956627154 (requires institutional sign-in at Scopus site)   71 Citations

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.

Author List

Zeng X, Shaikh FY, Harrison MK, Adon AM, Trimboli AJ, Carroll KA, Sharma N, Timmers C, Chodosh LA, Leone G, Saavedra HI

Authors

Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin
Anthony J. Trimboli PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Cell Proliferation
Cell Transformation, Neoplastic
Cells, Cultured
Centrosome
Cyclin D1
Cyclin-Dependent Kinase 4
Epithelial Cells
Female
Fibrocystic Breast Disease
Genes, ras
Humans
Mammary Glands, Animal
Mice
Mice, Transgenic
NIMA-Related Kinases
Signal Transduction