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

• Published in: Oncogene Vol. 29; no. 36; pp. 5103 - 5112
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.09.2010; Nature Publishing Group
• Subjects: 631/45/612/1223; 631/67/1347; 631/67/395; 631/80/128/1965; Aneuploidy; Animals; Apoptosis; Apoptosis - genetics; Biological and medical sciences; Breast cancer; c-Myc protein; Carcinogenesis; Cell Biology; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells, Cultured; Centrosome - metabolism; Centrosome - pathology; Centrosomes; Cyclin D1; Cyclin D1 - metabolism; Cyclin D1 - physiology; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase 4 - physiology; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Fibrocystic Breast Disease - genetics; Fibrocystic Breast Disease - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Genes, ras - genetics; Genes, ras - physiology; Genetic aspects; Genetics; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Internal Medicine; Mammary gland; Mammary gland diseases; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Molecular and cellular biology; Myc protein; NIMA-Related Kinases; Oncogenes; Oncology; Physiological aspects; Protein kinases; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Proteins; Ras genes; Regulatory proteins; Risk factors; Rodents; short-communication; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Tumorigenesis; Tumors; United States; centrosome amplification; cyclin D1; Nek2; Ras; Cdk4; mammary cancers; Breast disease; Enzyme; Transferases; Breast cancer; Malignant tumor; Cyclin D1; Carcinogenesis; Amplification; Mammary gland diseases; Epithelial cell; Mammary gland; Onc gene; Cyclin dependent kinase; Centrosome; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.253

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.