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Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1^sup -/-^ mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormalities were observed in the cyclin D1-rescued cells by spectral karyotyping and immunofluorescence. To assess cyclin D1 effects in vivo, we generated transgenic mice with acute and continuous mammary gland-targeted cyclin D1 expression. These transgenic mice presented with increased tumor prevalence and signature CIN gene profiles. Additionally, interrogation of gene expression from 2,254 human breast tumors revealed that cyclin D1 expression correlated with CIN in luminal B breast cancer. These data suggest that cyclin D1 contributes to CIN and tumorigenesis by directly regulating a transcriptional program that governs chromosomal stability.
Introduction
Chromosomal instability (CIN) in tumors (1-3) is by an elevated rate of gain or loss of whole chromosomes aneuploidy) and/or as structural chromosomal aberrations translocations, deletions, and duplications). Aneuploidy is one the most striking differences between cancer and normal The molecular mechanisms inducing CIN as well as the of CIN in tumor progression, invasion, and metastasis is understood (4, 5). Cell cycle-associated factors have been cated in CIN, including cyclin E (6). The relative enrichment of a molecular genetic signature of CIN-related genes has been used quantitate a CIN score (7); this signature includes AURKB (a ponent of the chromosomal passenger complex [CPC]), CENPP, MLFlIP (a component of the CENPA-NAC complex protein), ZWlO (a kinetochore-associated mitotic point protein), and CKAP2 (a mitotic spindle-associated (3) as well as the retinoblastoma (pRb) protein. centrosomes increase the frequency of dual attachment of 1 kinetochore to 2 spindle poles. Cyclin E activity promotes some duplication during S phase onset. Loss of pRb can also centrosome number and formation of micronuclei, leading mis-segregation of chromosomes and aneuploidy (8)....