The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2.
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.
Zeng
X
X
Department of Radiation Oncology, Emory University School of Medicine, and Emory Winship Cancer Institute, Atlanta, GA 30322, USA.
Shaikh
F Y
FY
Harrison
M K
MK
Adon
A M
AM
Trimboli
A J
AJ
Carroll
K A
KA
Sharma
N
N
Timmers
C
C
Chodosh
L A
LA
Leone
G
G
Saavedra
H I
HI
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism / Q000502:physiology*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005348:Fibrocystic Breast Disease / Q000235:genetics / Q000378:metabolism; D011905:Genes, ras / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D019938:Cyclin D1; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D051358:Cyclin-Dependent Kinase 4