Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression
Recent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic optio...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/12/1228 |
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| author | Rayanah Barnawi Samiyah Al-Khaldi Salma Majid Amal Qattan Tala Bakheet Mohannad Fallatah Hazem Ghebeh Nehad M. Alajez Monther Al-Alwan |
| author_facet | Rayanah Barnawi Samiyah Al-Khaldi Salma Majid Amal Qattan Tala Bakheet Mohannad Fallatah Hazem Ghebeh Nehad M. Alajez Monther Al-Alwan |
| author_sort | Rayanah Barnawi |
| collection | DOAJ |
| description | Recent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic options. Development of targeted therapies for TNBC requires better understanding of biology and signaling networks that promote disease progression. Fascin, an actin bundling protein, was identified as a key regulator of many signaling pathways that contribute to breast cancer progression. Herein, fascin ShRNA was used to generate stable fascin knockdown (FSCN1<sup>KD</sup>) in the MDA-MB-231 TNBC cell line and then were subjected to comprehensive mRNA and miRNA transcriptome analysis. We identified 129 upregulated and 114 downregulated mRNA transcripts, while 14 miRNAs were differentially expressed in FSCN1<sup>KD</sup>. Ingenuity pathway analysis (IPA) was used to predict the impact of differentially expressed transcripts on signaling pathways and functional categories and to construct miRNA-mRNA regulatory networks in the context of FSCN1 knockdown. Compared to FSCN1<sup>KD</sup>, fascin-positive (FSCN1<sup>CON</sup>) breast cancer cells showed enrichment in genes promoting cellular proliferation, migration, survival, DNA replication and repair. Expression of FSCN1<sup>high</sup> (identified in BRCA dataset from TCGA) in conjunction with elevated expression of the top 10 upregulated or decreased expression of the top 10 downregulated genes (identified in our FSCN1<sup>CON</sup> vs. FSCN1<sup>KD</sup>) correlates with worst survival outcome. Taken together, these data confirmed fascin’s role in promoting TNBC progression, and identified a novel opportunity for therapeutic interventions via targeting those FSCN1-related transcripts. |
| first_indexed | 2024-03-10T03:21:12Z |
| format | Article |
| id | doaj.art-2b9d45e3176c411cab455d3b094c7abe |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:21:12Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-2b9d45e3176c411cab455d3b094c7abe2023-11-23T10:02:44ZengMDPI AGPharmaceuticals1424-82472021-11-011412122810.3390/ph14121228Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer ProgressionRayanah Barnawi0Samiyah Al-Khaldi1Salma Majid2Amal Qattan3Tala Bakheet4Mohannad Fallatah5Hazem Ghebeh6Nehad M. Alajez7Monther Al-Alwan8Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi ArabiaNational Center for Biotechnology, Life Science and Environment Research Institute, King Abdulaziz City for Sciences and Technology, Riyadh 12354, Saudi ArabiaNational Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD 20892, USAMolecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11564, Saudi ArabiaMolecular Biomedicine Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11564, Saudi ArabiaNational Center for Biotechnology, Life Science and Environment Research Institute, King Abdulaziz City for Sciences and Technology, Riyadh 12354, Saudi ArabiaStem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi ArabiaTranslational Cancer and Immunity Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, QatarStem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi ArabiaRecent years have witnessed major progress in development of novel therapeutic agents such as chemotherapy, targeted therapy and immune checkpoint inhibitors for breast cancer. However, cancer-related death remains high especially in triple-negative breast cancer (TNBC) due limited therapeutic options. Development of targeted therapies for TNBC requires better understanding of biology and signaling networks that promote disease progression. Fascin, an actin bundling protein, was identified as a key regulator of many signaling pathways that contribute to breast cancer progression. Herein, fascin ShRNA was used to generate stable fascin knockdown (FSCN1<sup>KD</sup>) in the MDA-MB-231 TNBC cell line and then were subjected to comprehensive mRNA and miRNA transcriptome analysis. We identified 129 upregulated and 114 downregulated mRNA transcripts, while 14 miRNAs were differentially expressed in FSCN1<sup>KD</sup>. Ingenuity pathway analysis (IPA) was used to predict the impact of differentially expressed transcripts on signaling pathways and functional categories and to construct miRNA-mRNA regulatory networks in the context of FSCN1 knockdown. Compared to FSCN1<sup>KD</sup>, fascin-positive (FSCN1<sup>CON</sup>) breast cancer cells showed enrichment in genes promoting cellular proliferation, migration, survival, DNA replication and repair. Expression of FSCN1<sup>high</sup> (identified in BRCA dataset from TCGA) in conjunction with elevated expression of the top 10 upregulated or decreased expression of the top 10 downregulated genes (identified in our FSCN1<sup>CON</sup> vs. FSCN1<sup>KD</sup>) correlates with worst survival outcome. Taken together, these data confirmed fascin’s role in promoting TNBC progression, and identified a novel opportunity for therapeutic interventions via targeting those FSCN1-related transcripts.https://www.mdpi.com/1424-8247/14/12/1228fascinbreast cancermiRNApathway analysistranscriptomeIPA |
| spellingShingle | Rayanah Barnawi Samiyah Al-Khaldi Salma Majid Amal Qattan Tala Bakheet Mohannad Fallatah Hazem Ghebeh Nehad M. Alajez Monther Al-Alwan Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression Pharmaceuticals fascin breast cancer miRNA pathway analysis transcriptome IPA |
| title | Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression |
| title_full | Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression |
| title_fullStr | Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression |
| title_full_unstemmed | Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression |
| title_short | Comprehensive Transcriptome and Pathway Analyses Revealed Central Role for Fascin in Promoting Triple-Negative Breast Cancer Progression |
| title_sort | comprehensive transcriptome and pathway analyses revealed central role for fascin in promoting triple negative breast cancer progression |
| topic | fascin breast cancer miRNA pathway analysis transcriptome IPA |
| url | https://www.mdpi.com/1424-8247/14/12/1228 |
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