Crosstalk between FOXO3-FOMX1 axis and lipid metabolism in metastatic breast cancer

Abstract

The FOXO3 and FOXM1 transcription factors play important roles in regulating a wide range of biological processes. Deregulation of the FOXO3-FOXM1 axis is associated with cancer development. Recent data also linked the C. elegans Forkhead orthologue DAF-16 with FA metabolism. Here, my results show that metformin and 991 can increase FOXO3 protein expression, stability and activity through activation of the AMPK signalling pathway. AMPK activation also plays a key role in inhibiting breast cancer progression and in overcoming chemotherapeutic drug resistance through FOXO3, suggesting the possibility of the AMPK/FOXO3 signalling cascade as a novel therapeutic target, in particular for the multi-drug resistant breast cancer cell lines (MCF-7-EpiR and MCF-7-TaxR). In addition, my data have established a relationship between FOXM1 and FABP5. On one hand, FOXM1 promotes the transcription of FABP5 to influence cell metabolism and cancer development. On the other hand, FABP5 overexpression also induced FOXM1 expression and activity, suggesting a positive feedforward loop. My data also reveals a significant role for FABP5 in breast cancer carcinogenesis, progression as well as its involvement in the development of resistance to chemotherapeutic drugs. Furthermore, my data also shows that the expression of ACC2 in human breast cancer cell lines is partly regulated by FOXO3 and that FOXO3 is capable of inducing ACC2 expression at both the transcriptional and translational levels. However, due to the compensatory mechanism between ACC1 and ACC2 expression levels, current data cannot provide conclusive results showing whether FOXO3 regulates intracellular lipid contents directly through ACC2 or indirectly through ACC1. Nevertheless, these data reveal that ACC2 is a potential target for cancer therapy, although further investigations are needed. In short, these data open the possibility of targeting FA metabolism, possibly through FABP5 and ACC2 in MBC treatment.