Over-expression of a centrosomal serine/threonine kinase, STK15/BTAK, induces centrosome amplification, which results in chromosomal instability (CIN) in cell culture. In the present study, we investigated the correlation of STK15/BTAK mRNA expression with CIN and various clinicopathological factors in human breast cancer. STK15/BTAK mRNA levels were quantified by real-time PCR, and CIN values were determined by FISH analysis of chromosomes 1, 11 and 17 using centromeric probes. STK15/BTAK mRNA levels (0.310 ؎ 0.413, mean ؎ SD, n ؍ 47) in breast cancers were significantly (p < 0.01) higher than those in normal breast tissues (0.044 ؎ 0.029, n ؍ 9). Furthermore, breast cancers were divided into 3 groups (low, intermediate and high) according to STK15/BTAK mRNA expression levels. CIN values of the low-expression group (27.9 ؎ 12.6%, n ؍ 18) were significantly (p < 0.01) higher than those of normal breast tissues (9.2 ؎ 2.6%, n ؍ 6), and those of the high-expression group (38.0 ؎ 12.7%, n ؍ 14) were significantly (p < 0.05) higher than those of the low-expression group. STK15/BTAK mRNA expression showed a significant (p < 0.05) correlation with high histological grade and negativity of estrogen and progesterone receptors. Our results demonstrate that STK15/BTAK mRNA is over-expressed in the majority of breast cancers and its over-expression is significantly associated with CIN, implicating STK15/BTAK in carcinogenesis through induction of CIN. STK15/BTAK mRNA levels might be useful as an indicator of poor prognosis and resistance to endocrine therapy. © 2001 Wiley-Liss, Inc.
Key words: STK15/BTAK; real-time RT-PCR; chromosomal instability; centrosome; breast cancerA centrosomal serine/threonine kinase, serine/threonine kinase 15/breast tumor amplified kinase (STK15/BTAK, approved gene symbols are aurora2, ARK1, AIK1), has been identified as an oncogene. [1][2][3][4] It has been shown by in vitro study using NIH-3T3 cells that over-expression of STK15/BTAK induces amplification of centrosomes. 4 Since the centrosomes play an essential role in chromosomal segregation during cell division through establishment of bipolar spindles, their amplification leads to chromosomal instability (CIN). These changes induced by STK15/BTAK overexpression are speculated to result in the transformation of cells. 4 Amplification of the STK15/BTAK gene as well as over-expression of STK15/BTAK mRNA and protein have been reported in human breast cancers, 1,4,5 indicating that STK15/BTAK may be involved in the pathogenesis of human breast cancer. In these reports, however, the most important issue, i.e., association of STK15/BTAK overexpression with CIN, has never been studied. If STK15/BTAK overexpression plays a significant role in pathogenesis, breast cancers with STK15/BTAK over-expression are supposed to show CIN. In the present study, we quantified STK15/BTAK mRNA levels using realtime PCR and compared them with CIN values determined by FISH analysis of chromosomes 1, 11 and 17 in human breast cancers. Correlations of STK15...