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Polo-like kinase 1 inhibitors differentiate triple-negative breast cancer towards a luminal cell fate

ABSTRACT: Transcriptomic profiling was applied to investigate the effects of polo-like kinase 1 inhibition in triple-negative breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184295 | GEO | 2022/08/29

REPOSITORIES: GEO

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Polo-like kinase 1 inhibitors differentiate triple-negative breast cancer towards a luminal cell fate

Project description:Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, triple-negative is the subtype that lacks the expression of major differentiation markers (i.e. estrogen receptor [ER]), ant its high cellular plasticity results in higher aggressiveness and poor prognosis compared to other subtypes. Whether plasticity poses a vulnerability to cancer cells remains elusive. Here, we show that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer. Using a high-throughput reporter drug screen with 9,501 compounds, we identify three polo-like kinase 1 (PLK1) inhibitors as major inducers of ER protein expression and downstream activity in triple-negative breast cancer cells via the transcription factor BATF. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest and ultimately cell death. Notably, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth both in cell line and patient-derived xenograft models. In addition, genes upregulated upon PLK1 inhibition are correlated with expression in normal breast tissue and confer better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition might be an alternative strategy to treat triple-negative breast cancer.

2022-08-23 | PXD028495 | Pride

Two Forkhead transcription factors regulate cardiac progenitor cell divisions by a Polo kinase-dependent pathway

Project description:The development of a complex organ requires the proper differentiation and production of appropriate numbers of each of its constituent cell types, as well as their correct positioning within the organ. During Drosophila cardiogenesis, all three of these processes are controlled by jumeau (jumu) and Checkpoint suppressor homologue (CHES-1-like), two genes encoding forkhead transcription factors that were discovered utilizing an integrated genetic, genomic and computational strategy which identified 70 novel genes expressed in the developing Drosophila heart. Both jumu and CHES-1-like are required during asymmetric cell division for the derivation of two distinct cardiac cell types from their mutual precursor, and in symmetric cell division to produce yet a third type of heart cell. jumu and CHES-1-like control the division of cardiac progenitors by regulating the activity of Polo, a kinase involved in multiple steps of mitosis. This pathway demonstrates how transcription factors integrate diverse developmental processes during organogenesis. GFP-positive cells were profiled from Stage 11-12 Drosophila embryos of the following two genotypes: twi-GAL4 UAS-2EGFP/UAS-jumu and twi-GAL4 UAS-2EGFP

2012-01-30 | E-GEOD-34946 | biostudies-arrayexpress

Down-regulation of Polo-like kinase 4 (PLK4) induces G1 arrest via activation of the p38/p53/p21 signalling pathway in bladder

Project description:We demonstrate that Polo-like kinase 4(PLK4) is overexpressed in human bladder cancer (BC) cell lines and tissues, and its overexpression correlates with poor prognosis. PLK4 inhibition suppresses BC cell growth and induces G1 phase arrest via activating p38/p53/p21 pathway in vitro and in vivo. The data suggest that PLK4 might serve as a novel molecular target for BC treatment.

2021-07-29 | GSE180958 | GEO

Development of cyclic peptomer inhibitors targeting the polo-box domain of polo-like kinase 1.

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Linear Regression QSAR Models for Polo-Like Kinase-1 Inhibitors.

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Common profiles of Notch signaling differentiate disease-free survival in luminal type A and triple negative breast cancer.

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Development of Highly Selective 1,2,3-Triazole-containing Peptidic Polo-like Kinase 1 Polo-box Domain-binding Inhibitors.

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Computational design of targeted inhibitors of polo-like kinase 1 (plk1).

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Threonine-4 of Mammalian RNA Polymerase II CTD is Targeted by Polo-like Kinase-3 and Required for Transcriptional Elongation

Project description:Eukaryotic RNA polymerase II (Pol II) has evolved an array of heptad repeats with the consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7 at the carboxy-terminal domain (CTD) of the large subunit (Rpb1). Differential phosphorylation of Ser2, Ser5, and Ser7 in the 5’ and 3’ regions of genes coordinates the binding of transcription and RNA processing factors to the initiating and elongating polymerase complexes. Here, we report phosphorylation of Thr4 by Polo-like-kinase-3 in mammalian cells. ChIPseq analyses indicate an increase of Thr4-P levels in the 3’ region of genes occurring subsequently to an increase of Ser2-P levels. A Thr4/Ala mutant of Pol II displays a lethal phenotype. This mutant reveals a global defect in RNA elongation, while initiation is largely unaffected. Since Thr4 replacement mutants are viable in yeast we conclude that this amino acid has evolved an essential function(s) in the CTD of Pol II for gene transcription in mammalian cells.

2012-06-04 | GSE37519 | GEO

Polo-like kinase 1 (Plk1) inhibition synergizes with taxanes in triple negative breast cancer.

Project description: Not available

| S-EPMC6872222 | biostudies-literature