TY - JOUR
T1 - Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel
AU - Elango, Ramesh
AU - Vishnubalaji, Radhakrishnan
AU - Shaath, Hibah
AU - Alajez, Nehad M.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/3/12
Y1 - 2021/3/12
N2 - 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. TNBC patients exhibit variable responses to therapy, suggesting an underlying molecular heterogeneity. Herein, we classified TNBC into seven molecular subtypes with distinct molecular signatures. Our data highlight pivotal roles for TTK, TPX2, and LRP8 in TNBC biology and their sensitivity to paclitaxel, suggesting their potential utilization as therapeutic targets.
AB - 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. TNBC patients exhibit variable responses to therapy, suggesting an underlying molecular heterogeneity. Herein, we classified TNBC into seven molecular subtypes with distinct molecular signatures. Our data highlight pivotal roles for TTK, TPX2, and LRP8 in TNBC biology and their sensitivity to paclitaxel, suggesting their potential utilization as therapeutic targets.
KW - LRP8
KW - TNBC
KW - TPX2
KW - TTK
KW - UBE2C
KW - bioinformatics
KW - classification
KW - gene signature
KW - heterogeneity
KW - transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85100953682&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2021.01.013
DO - 10.1016/j.omtm.2021.01.013
M3 - Article
AN - SCOPUS:85100953682
SN - 2329-0501
VL - 20
SP - 601
EP - 614
JO - Molecular Therapy Methods and Clinical Development
JF - Molecular Therapy Methods and Clinical Development
ER -