Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation

Abstract

Summary Our recent analysis of gastric cancers using comparative genomic hybridization (CGH) revealed a novel high frequent copy number increase in the long arm of chromosome 20. Tumour-amplified kinase BTAK was recently cloned from breast cancers and mapped on 20q13 as a target gene for this amplification in human breast cancers. In the study presented here, we analysed BTAK copy-number and expression, and their relation to the ploidy pattern in 72 primary gastric cancers. Furthermore, wild-type BTAK and its deletion mutants were transfected to gastric cancers to examine changes in cell proliferation and DNA ploidy pattern. Evaluation of 72 unselected primary gastric cancers found BTAK amplification in 5% and overexpression in more than 50%. All four clinical samples with BTAK amplification showed aneuploidy and poor prognosis. Transfection of BTAK in near-diploid gastric cancers induced another aneuploid cell population. In contrast, the c-terminal-deleted mutant of BTAK induced no effect in DNA ploidy pattern and inhibited gastric cancer cell proliferation. These results suggest that BTAK may be involved in gastric cancer cell aneuploid formation, and is a candidate gene for the increase in the number of copies of the 20q, and thus may contribute to an increase in the malignant phenotype of gastric cancer.

Genetic alterations in 102 primary gastric cancers by comparative genomic hybridization: gain of 20q and loss of 18q are associated with tumor progression

“…52 Amplification and overexpression of the BTAK gene, which encodes breast tumor-amplified kinase (identical to aurora2, ARK1 and STK15), have been reported in primary gastric adenocarcinomas that were associated with aneuploidy and poor prognosis. 47 Moreover, amplification and overexpression of the AIB1 (amplified in breast cancer 1) gene, a member of the steroid receptor coactivator family, appears to be useful as a marker of poor prognosis in gastric cancer. 49 Recently, it was reported that TOP1, TFAP2C and NCOA3 (AIB1) might be prognostic indicators in breast cancer.…”

Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A

“…Aurora-A is overexpressed in many cancer types and mapped to chromosome 20q13 region, which is frequently amplified in many human cancers (Tanaka et al, 1999;Gritsko et al, 2003;Li et al, 2003). Overexpression of Aurora-A significantly correlates with the induction of aneuploidy, centrosome anomaly, poor prognosis and invasiveness of the primary human tumors and of experimental tumors in animal model systems (Sakakura et al, 2001;Buschhorn et al, 2005). Aurora-A levels and functions are regulated by multiple mechanisms such as gene amplification, transcription, post-translational modifications including phosphorylation/dephosphorylation and proteolysis through proteasome-dependent pathway (Honda et al, 2000;Walter et al, 2000).…”

Function and regulation of Aurora/Ipl1p kinase family in cell division

“…Ectopic expression of Aurora-A in mouse NIH3T3 cells display the phenotype of abnormal centrosomes replication and cell transformation. Moreover, it has been shown that over-expression of Aurora-A in diploid human breast epithelial cells causes aberrant centrosome replication, as well as induction of aneuploidy, indicating that there are intrinsic links between aberrant regulation of Aurora-A activity and pathogeneses of aneuploidy and chromosomal instability [70,71]. Recently, Meraldi et al show that over-expression of Aurora-A gave rise to centrosome amplification and polyploid [72].…”