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Transcriptome profiling identified differentially expressed genes and pathways associated with tamoxifen resistance
1National Engineering Research Center for Miniaturized Detection Systems, College of Life Science, Northwest University, Xi'an, PR China.
Abstract:
Tamoxifen (TAM) resistance is an important clinical problem in the treatment of breast cancer. In order to identify the mechanism of TAM resistance for estrogen receptor (ER)-positive breast cancer, we screened the transcriptome using RNA-seq and compared the gene expression profiles between the MCF-7 mamma carcinoma cell line and the TAM-resistant cell line TAMR/MCF-7, 52 significant differential expression genes (DEGs) were identified including SLIT2, ROBO, LHX, KLF, VEGFC, BAMBI, LAMA1, FLT4, PNMT, DHRS2, MAOA and ALDH. The DEGs were annotated in the GO, COG and KEGG databases. Annotation of the function of the DEGs in the KEGG database revealed the top three pathways enriched with the most DEGs, including pathways in cancer, the PI3K-AKT pathway, and focal adhesion. Then we compared the gene expression profiles between the Clinical progressive disease (PD) and the complete response (CR) from the cancer genome altas (TCGA). 10 common DEGs were identified through combining the clinical and cellular analysis results. Protein-protein interaction network was applied to analyze the association of ER signal pathway with the 10 DEGs. 3 significant genes (GFRA3, NPY1R and PTPRN2) were closely related to ER related pathway. These significant DEGs regulated many biological activities such as cell proliferation and survival, motility and migration, and tumor cell invasion. The interactions between these DEGs and drug resistance phenomenon need to be further elucidated at a functional level in further studies. Based on our findings, we believed that these DEGs could be therapeutic targets, which can be explored to develop new treatment options.
Insights
Tamoxifen resistance in breast cancer involves specific gene expression changes. Identifying these differentially expressed genes may lead to new therapeutic targets for improving treatment outcomes.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Tamoxifen (TAM) resistance is a significant clinical challenge in treating estrogen receptor (ER)-positive breast cancer.
- Understanding the molecular mechanisms underlying TAM resistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To identify differentially expressed genes (DEGs) associated with TAM resistance in ER-positive breast cancer.
- To explore the functional roles of these DEGs and their potential as therapeutic targets.
Main Methods:
- RNA sequencing (RNA-seq) was used to compare gene expression profiles between MCF-7 and TAM-resistant MCF-7 (TAMR/MCF-7) cell lines.
- Gene Ontology (GO), Clusters of Orthologous Genes (COG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were utilized for DEG annotation.
- Comparative analysis with The Cancer Genome Atlas (TCGA) data (progressive disease vs. complete response) and protein-protein interaction network analysis were performed.
Main Results:
- 52 significant DEGs were identified in TAM-resistant cells, including SLIT2, ROBO, and VEGFC.
- KEGG analysis highlighted enriched pathways in cancer, PI3K-AKT signaling, and focal adhesion.
- Ten common DEGs were found between cellular and clinical analyses, with GFRA3, NPY1R, and PTPRN2 showing close association with the ER pathway.
Conclusions:
- The identified DEGs regulate critical biological processes such as cell proliferation, survival, motility, migration, and invasion.
- These DEGs represent potential therapeutic targets for overcoming TAM resistance in breast cancer.
- Further functional studies are warranted to elucidate the precise interactions between DEGs and drug resistance mechanisms.
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