Low molecular weight cyclin E overexpression shortens mitosis, leading to chromosome missegregation and centrosome amplification.
Overexpression of the low molecular weight isoforms (LMW-E) of cyclin E induces chromosome instability; however, the degree to which these tumor-specific forms cause genomic instability differs from that of full-length cyclin E (EL), and the underlying mechanism(s) has yet to be elucidated. Here, we show that EL and LMW-E overexpression impairs the G(2)-M transition differently and leads to different degrees of chromosome instability in a breast cancer model system. First, the most significant difference is that EL overexpression prolongs cell cycle arrest in prometaphase, whereas LMW-E overexpression reduces the length of mitosis and accelerates mitotic exit. Second, LMW-E-overexpressing cells are binucleated or multinucleated with amplified centrosomes, whereas EL-overexpressing cells have the normal complement of centrosomes. Third, LMW-E overexpression causes mitotic defects, chromosome missegregation during metaphase, and anaphase bridges during anaphase, most of which are not detected on EL induction. LMW-E induces additional mitotic defects in cooperation with p53 loss in both normal and tumor cells. Fourth, LMW-E-overexpressing cells fail to arrest in the presence of nocodazole. Collectively, the mitotic defects mediated by LMW-E induction led to failed cytokinesis and polyploidy, suggesting that LMW-E expression primes cells to accrue chromosomal instability by shortening the length of mitosis. Lastly, LMW-E expression in human breast cancer tissues correlates with centrosome amplification and higher nuclear grade. These results suggest that LMW-E overexpression leads to higher centrosome numbers in breast cancer, which is a prerequisite for genomic instability.
Bagheri-Yarmand
Rozita
R
Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. ryarmand@mdanderson.org
Biernacka
Anna
A
Hunt
Kelly K
KK
Keyomarsi
Khandan
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018385:Centrosome / Q000473:pathology*; D043171:Chromosomal Instability; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics*; D008970:Molecular Weight; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011003:Ploidies
D014408:Biomarkers, Tumor; C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins