FOXM1 recruits nuclear Aurora kinase A to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells.

Substantial evidence suggests that breast cancer initiation, recurrence and drug resistance is supported by breast cancer stem cells (BCSCs). Recently, we reported a novel role of Aurora kinase A (AURKA) in BCSCs, as a transactivating co-factor in the induction of the c-Myc oncoprotein. However, the mode of action and transcriptional network of nuclear AURKA in BCSCs remain unknown. Here, we report that nuclear AURKA can be recruited by Forkhead box subclass M1 (FOXM1) as a co-factor to transactivate FOXM1 target genes in a kinase-independent manner. In addition, we show that AURKA and FOXM1 participate in a tightly coupled positive feedback loop to enhance BCSC phenotype. Indeed, kinase-dead AURKA can effectively transactivate the FOXM1 promoter through a Forkhead response element, whereas FOXM1 can activate AURKA expression at the transcriptional level in a similar manner. Consistently, breast cancer patient samples portrayed a strong and significant correlation between the expression levels of FOXM1 and AURKA. Moreover, both FOXM1 and AURKA were essential for maintaining the BCSC population. Finally, we demonstrated that the AURKA inhibitor AKI603 and FOXM1 inhibitor thiostrepton acted synergistically to inhibit cytoplasmic AURKA activity and disrupt the nuclear AURKA/FOXM1-positive feedback loop, respectively, resulting in a more effective inhibition of the tumorigenicity and self-renewal ability of BCSCs. Collectively, our study uncovers a previously unknown tightly coupled positive feedback signalling loop between AURKA and FOXM1, crucial for BCSC self-renewal. Remarkably, our data reveal a novel potential therapeutic strategy for targeting both the cytoplasmic and nuclear AURKA function to effectively eliminate BCSCs, so as to overcome both breast cancer and drug resistance.

The social cost of smoking in Singapore.

This study provides estimates for the cost of smoking in Singapore in 1997.A first attempt for Singapore, the paper reports on two different methods used, namely, the human capital approach and the demographic approach. These two measures are similar in that they compare the economic cost of smoking in the actual situation with the hypothetical alternative where there had been no smoking. The direct cost of smoking includes the amount spent on hospital care for five main diseases related to smoking whilst the indirect cost includes the value of lost income. The mortality cost of smoking is derived from the aetiological fractions of these diseases. The results from the human capital approach show that the social cost of smoking in 1997 ranged from S$673 million to S$839 million. Assuming there has been no smoking since 1990, calculations from the demographic approach indicate that national output would have increased by S$614 million in 1998. Nonetheless, the results from both approaches show that most of the cost of smoking is incurred by males.