Tamoxifen induces fatty liver disease in breast cancer through the MAPK8/FoxO pathway

Background: Prevention of metabolic complications of long-term adjuvant endocrine therapy in breast cancers remained a challenge. We aimed to investigate the molecular mechanism in the development of tamoxifen (TAM)-induced fatty liver in both Estrogen Receptor (ER)-positive and ER-negative breast Cancer.

Methods and results: First, the direct protein targets (DPTs) of TAM were identified using DrugBank5.1.7. We found that mitogen-activated protein kinase 8 (MAPK8) was one DPT of TAM. We identified significant genes in breast Cancer and fatty liver disease (FLD) using the MalaCards human disease database. Next, we analyzed the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of those significant genes in breast Cancer and FLD using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). We found that overlapping KEGG pathways in these two diseases were MAPK signaling pathway, Forkhead box O (FoxO) signaling pathway, HIF-1 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and PI3K-Akt signaling pathway. Furthermore, the KEGG Mapper showed that the MAPK signaling pathway was related to the FoxO signaling pathway. Finally, the functional relevance of breast Cancer and TAM-induced FLD was validated by Western blot analysis. We verified that TAM may induce fatty liver in breast Cancer through the MAPK8/FoxO signaling pathway.

Conclusion: Bioinformatics analysis combined with conventional experiments may improve our understanding of the molecular mechanisms underlying side effects of Cancer drugs, thereby making this method a new paradigm for guiding future studies on this issue.