Guanylate-binding protein-1 is a potential new therapeutic target for triple-negative breast cancer

Author(s)

Quintero, Melissa ^[1] ; Adamoski, Douglas ^{[1, 2]} ; dos Reis, Larissa Menezes ^{[1, 2]} ; Rodrigues Ascencao, Carolline Fernanda ^{[1, 2]} ; Sousa de Oliveira, Krishina Ratna ^{[1, 2]} ; Goncalves, Kaliandra de Almeida ^[1] ; Dias, Marilia Meira ^[1] ; Carazzolle, Marcelo Falsarella ^[3] ; Gomes Dias, Sandra Martha ^[1]

Affiliation

^[1] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083970 Campinas, SP - Brazil

^[2] Univ Campinas UNICAMP, Grad Program Genet & Mol Biol, Inst Biol, Campinas, SP - Brazil

^[3] Univ Campinas UNICAMP, LGE, Inst Biol, Campinas, SP - Brazil

• Document type: Journal article
• Source: BMC CANCER; v. 17, NOV 7 2017.
• Web of Science Citations: 8

Abstract

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. (AU)

• FAPESP's process: 14/17820-3 - Post-transcriptional regulation of glutaminase enzyme by HuR and its relationship with high glutaminolytic levels in tumors
• Grantee: Douglas Adamoski Meira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 15/25832-4 - Metabolic regulation of genetic and epigenetic control of gene expression
• Grantee: Sandra Martha Gomes Dias
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/18061-9 - Study of alternative anaplerotic sources of the TCA as new targets against triple-negative breast cancer
• Grantee: Larissa Menezes dos Reis
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 12/09452-9 - Transcriptome and metabolomic studies of cancer cells as a tool for understanding the metabolic adaptation process
• Grantee: Melissa Quintero Escobar
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 12/11577-4 - Studies of the metabolic alterations related to the PI3K-Akt pathway and RAS oncogene co-activation.
• Grantee: Marília Meira Dias
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 09/53853-5 - Acquisition of a high-performance platform for computational analyses applied to the field of medicine
• Grantee: Wilson Araújo da Silva Junior
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 13/23510-4 - Understanding how PI3K/AKt/mTOR and AMPK signaling pathways affect glutaminase activity.
• Grantee: Carolline Fernanda Rodrigues Ascenção
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/06512-6 - Epigenetic study of histone demethylases enzymes Fe (II) and ±-ketoglutarate dependent of the jumonji family in the context of tumoral metabolism and glutaminase activity
• Grantee: Krishina Ratna Sousa de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/15968-3 - Understanding the glutaminase functional regulation and the development of inhibitors as new approaches to cancer therapy
• Grantee: Sandra Martha Gomes Dias
• Support Opportunities: Regular Research Grants