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 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.
Other Information
Published in: Molecular Therapy - Methods & Clinical Development
License: http://creativecommons.org/licenses/by-nc-nd/4.0/
See article on publisher's website: https://dx.doi.org/10.1016/j.omtm.2021.01.013
Funding
Open Access funding provided by the Qatar National Library.
History
Language
- English
Publisher
ElsevierPublication Year
- 2021
License statement
This Item is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Institution affiliated with
- Hamad Bin Khalifa University
- College of Health and Life Sciences - HBKU
- Qatar Biomedical Research Institute - HBKU
- Cancer Research Center - QBRI