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Guanylate-binding protein-1 is a potential new therapeutic target for triple-negative breast cancer
Melissa Quintero1, Douglas Adamoski1,2, Larissa Menezes Dos Reis1,2
1Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, São Paulo, 13083-970, Brazil.
Background:
Triple-negative breast cancer (TNBC) is characterized by a lack of estrogen and progesterone receptor expression (ESR and PGR, respectively) and an absence of human epithelial growth factor receptor (ERBB2) amplification. Approximately 15-20% of breast malignancies are TNBC. Patients with TNBC often have an unfavorable prognosis. In addition, TNBC represents an important clinical challenge since it does not respond to hormone therapy.
Methods:
In this work, we integrated high-throughput mRNA sequencing (RNA-Seq) data from normal and tumor tissues (obtained from The Cancer Genome Atlas, TCGA) and cell lines obtained through in-house sequencing or available from the Gene Expression Omnibus (GEO) to generate a unified list of differentially expressed (DE) genes. Methylome and proteomic data were integrated to our analysis to give further support to our findings. Genes that were overexpressed in TNBC were then curated to retain new potentially druggable targets based on in silico analysis. Knocking-down was used to assess gene importance for TNBC cell proliferation.
Results:
Our pipeline analysis generated a list of 243 potential new targets for treating TNBC. We finally demonstrated that knock-down of Guanylate-Binding Protein 1 (GBP1 ), one of the candidate genes, selectively affected the growth of TNBC cell lines. Moreover, we showed that GBP1 expression was controlled by epidermal growth factor receptor (EGFR) in breast cancer cell lines.
Conclusions:
We propose that GBP1 is a new potential druggable therapeutic target for treating TNBC with enhanced EGFR expression.
Insights
Guanylate-Binding Protein 1 (GBP1) is a potential new therapeutic target for triple-negative breast cancer (TNBC). Targeting GBP1 selectively affected TNBC cell growth, suggesting its role in cancer proliferation.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) lacks estrogen/progesterone receptors and ERBB2 amplification, presenting a poor prognosis and resistance to hormone therapy.
- TNBC accounts for 15-20% of breast cancers and poses a significant clinical challenge due to limited treatment options.
Purpose of the Study:
- To identify novel druggable therapeutic targets for triple-negative breast cancer.
- To explore the role of overexpressed genes in TNBC proliferation and identify potential therapeutic strategies.
Main Methods:
- Integrated high-throughput mRNA sequencing (RNA-Seq) data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify differentially expressed genes.
- Utilized methylome and proteomic data to support findings and performed in silico analysis to identify druggable targets.
- Employed gene knockdown experiments to assess the impact of candidate genes on TNBC cell proliferation.
Main Results:
- Identified 243 potential new therapeutic targets for TNBC.
- Demonstrated that Guanylate-Binding Protein 1 (GBP1) knockdown selectively inhibited TNBC cell line growth.
- Showed that epidermal growth factor receptor (EGFR) controls GBP1 expression in breast cancer cell lines.
Conclusions:
- Guanylate-Binding Protein 1 (GBP1) is proposed as a novel druggable therapeutic target for TNBC.
- GBP1 targeting offers a potential treatment strategy for TNBC, particularly in cases with enhanced EGFR expression.
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