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

Abstract

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.

Evidence for Adverse Effects on Liver Development and Regeneration in Zebrafish by Decabromodiphenyl Ethane

“…The obviously changed genes were mainly related to the MAPK signaling pathway ( mycb and gadd45ba ), Fox O signaling pathway ( rag1 , cdkn1a , and gadd45ba ), cell cycle ( mycb , cdkn1a , and gadd45ba ), and apoptosis ( gadd45ba ) (Figure C). Similar to our results, a previous study reported that the inhibition of MAPK signaling pathways caused disturbance of the FoxO signaling pathway and finally led to cell cycle arrest and apoptosis in pancreatic cancer cells. , Notably, gadd45ba was identified as the hub gene within the above-mentioned signaling pathways, followed by cdkn1a and mycb . The Gadd45 family of proteins has been shown to be a sensitive stress sensor for various physiological and environmental pollutants .…”

Analysis of Breast Cancer Based on the Dysregulated Network

“…And, these pathways have crosstalk with other common cancer pathways ( Chen and Wang, 2012 ; Sato, 2013 ). For example, Pathways in cancer, Focal adhesion ( Ocak et al, 2010 ; Gari et al, 2016 ; Gu et al, 2018 ; Gong et al, 2019 ), Cell cycle, FoxO signaling pathway ( Mohd et al, 2017 ; Gong et al, 2020 ), Choline metabolism in cancer, Oxytocin signaling pathway ( Cassoni et al, 1994 ; Pequeux, 2002 ; Wang et al, 2020 ), ErbB signaling pathway ( Liu et al, 2008 ; Aline et al, 2015 ), and JAK-STAT signaling pathway ( Hernández-Vargas et al, 2011 ; Wang et al, 2018 ; Na and Balko, 2019 ).…”

Value of negatively correlated miR-205-5p/HMGB3 and miR-96-5p/FOXO1 on the diagnosis of breast cancer and benign breast diseases

“…Functional analysis of candidate DE-miRNAs and DE-mRNAs selected from TCGA and GEO databases revealed that they were related to the classic p53, FoxO, TGF-beta, and hippo pathways, consistent with previous studies. 19 , 20 , 21 , 22 KEGG pathway analysis of proteoglycans in cancer has attracted increasing attention. Proteoglycans affect malignant cells and the tumor microenvironment in both solid and hematopoietic cancers.…”