The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2
| Autor: | Gustavo Leone, KA Carroll, Mary K. Harrison, Cynthia Timmers, FY Shaikh, Lewis A. Chodosh, Xiangbin Zeng, Arsene M. Adon, Harold I. Saavedra, Anthony J. Trimboli, Nidhi Sharma |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Mammary gland Apoptosis Mice Transgenic Protein Serine-Threonine Kinases Biology medicine.disease_cause Article Mice Mammary Glands Animal Cyclin D1 Cyclin-dependent kinase Genetics medicine Animals Humans NIMA-Related Kinases Fibrocystic Breast Disease Molecular Biology Cells Cultured Cell Proliferation Centrosome Mammary tumor Oncogene Cyclin-dependent kinase 4 Cyclin-Dependent Kinase 4 Epithelial Cells Cyclin E1 Cell Transformation Neoplastic Genes ras medicine.anatomical_structure biology.protein Cancer research Female Carcinogenesis Signal Transduction |
| Zdroj: | Oncogene. 29:5103-5112 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2010.253 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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