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Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel
Triple-negative breast cancer (TNBC) patients exhibit variable responses to chemotherapy, suggesting an underlying molecular heterogeneity. In the current study, we analyzed publicly available transcriptome data from 360 TNBC and 88 normal breast tissues, which revealed activation of nucleosome and...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society of Gene & Cell Therapy
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899947/ https://www.ncbi.nlm.nih.gov/pubmed/33665229 http://dx.doi.org/10.1016/j.omtm.2021.01.013 |
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author | Elango, Ramesh Vishnubalaji, Radhakrishnan Shaath, Hibah Alajez, Nehad M. |
author_facet | Elango, Ramesh Vishnubalaji, Radhakrishnan Shaath, Hibah Alajez, Nehad M. |
author_sort | Elango, Ramesh |
collection | PubMed |
description | Triple-negative breast cancer (TNBC) patients exhibit variable responses to chemotherapy, suggesting an underlying molecular heterogeneity. In the current study, we analyzed publicly available transcriptome data from 360 TNBC and 88 normal breast tissues, which revealed activation of nucleosome and cell cycle as the hallmarks of TNBC. Mechanistic network analysis identified activation of FOXM1 and ERBB2, and suppression of TP53 and NURP1 networks in TNBC. Employing Iterative Clustering and Guide-gene Selection (ICGS), Uniform Manifold Approximation and Projection (UMAP), and dimensionality reduction analyses, we classified TNBC into seven molecular subtypes, each exhibiting a unique molecular signature, including immune infiltration (CD19, CD8, and macrophages) and mesenchymal signature, which correlated with variable disease outcomes in a larger cohort (1,070) of BC. Mechanistically, depletion of TTK, TPX2, UBE2C, CDCA7, MELK, NFE2L3, DDX39A, and LRP8 led to substantial inhibition of colony formation of TNBC models, which was further enhanced in the presence of paclitaxel. Our data provide novel insights into the molecular heterogeneity of TNBC and identified TTK, TPX2, UBE2C, and LRP8 as main drivers of TNBC tumorigenesis. |
format | Online Article Text |
id | pubmed-7899947 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-78999472021-03-03 Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel Elango, Ramesh Vishnubalaji, Radhakrishnan Shaath, Hibah Alajez, Nehad M. Mol Ther Methods Clin Dev Original Article Triple-negative breast cancer (TNBC) patients exhibit variable responses to chemotherapy, suggesting an underlying molecular heterogeneity. In the current study, we analyzed publicly available transcriptome data from 360 TNBC and 88 normal breast tissues, which revealed activation of nucleosome and cell cycle as the hallmarks of TNBC. Mechanistic network analysis identified activation of FOXM1 and ERBB2, and suppression of TP53 and NURP1 networks in TNBC. Employing Iterative Clustering and Guide-gene Selection (ICGS), Uniform Manifold Approximation and Projection (UMAP), and dimensionality reduction analyses, we classified TNBC into seven molecular subtypes, each exhibiting a unique molecular signature, including immune infiltration (CD19, CD8, and macrophages) and mesenchymal signature, which correlated with variable disease outcomes in a larger cohort (1,070) of BC. Mechanistically, depletion of TTK, TPX2, UBE2C, CDCA7, MELK, NFE2L3, DDX39A, and LRP8 led to substantial inhibition of colony formation of TNBC models, which was further enhanced in the presence of paclitaxel. Our data provide novel insights into the molecular heterogeneity of TNBC and identified TTK, TPX2, UBE2C, and LRP8 as main drivers of TNBC tumorigenesis. American Society of Gene & Cell Therapy 2021-01-26 /pmc/articles/PMC7899947/ /pubmed/33665229 http://dx.doi.org/10.1016/j.omtm.2021.01.013 Text en © 2021 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Elango, Ramesh Vishnubalaji, Radhakrishnan Shaath, Hibah Alajez, Nehad M. Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel |
title | Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel |
title_full | Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel |
title_fullStr | Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel |
title_full_unstemmed | Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel |
title_short | Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel |
title_sort | molecular subtyping and functional validation of ttk, tpx2, ube2c, and lrp8 in sensitivity of tnbc to paclitaxel |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899947/ https://www.ncbi.nlm.nih.gov/pubmed/33665229 http://dx.doi.org/10.1016/j.omtm.2021.01.013 |
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