A high-throughput drug screen reveals means to differentiate triple-negative breast cancer.

Autor: Vulin M; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Jehanno C; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland., Sethi A; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.; Swiss Institute of Bioinformatics, Basel, Switzerland., Correia AL; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Obradović MMS; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Couto JP; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Coissieux MM; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Diepenbruck M; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland., Preca BT; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland., Volkmann K; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland., der Maur PA; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland., Schmidt A; Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland., Münst S; Institute of Pathology and Medical Genetics, University Hospital Basel, University of Basel, Basel, Switzerland., Sauteur L; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland., Kloc M; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Swiss Institute of Bioinformatics, Basel, Switzerland., Palafox M; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland., Britschgi A; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Unterreiner V; Novartis Institutes for Biomedical Research, Basel, Switzerland., Galuba O; Novartis Institutes for Biomedical Research, Basel, Switzerland., Claerr I; Novartis Institutes for Biomedical Research, Basel, Switzerland., Lopez-Romero S; Novartis Institutes for Biomedical Research, Basel, Switzerland., Galli GG; Novartis Institutes for Biomedical Research, Basel, Switzerland., Baeschlin D; Novartis Institutes for Biomedical Research, Basel, Switzerland., Okamoto R; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Soysal SD; Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Breast Cancer Center, University Hospital Basel, University of Basel, Basel, Switzerland., Mechera R; Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Breast Cancer Center, University Hospital Basel, University of Basel, Basel, Switzerland., Weber WP; Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Breast Cancer Center, University Hospital Basel, University of Basel, Basel, Switzerland., Radimerski T; Novartis Institutes for Biomedical Research, Basel, Switzerland., Bentires-Alj M; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland. m.bentires-alj@unibas.ch.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. m.bentires-alj@unibas.ch.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 Sep; Vol. 41 (39), pp. 4459-4473. Date of Electronic Publication: 2022 Aug 25.
DOI: 10.1038/s41388-022-02429-0
Abstrakt: Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, the subtype triple-negative lacks expression of major differentiation markers, e.g., estrogen receptor α (ERα), and its high cellular plasticity results in greater aggressiveness and poorer prognosis than other subtypes. Whether plasticity itself represents a potential vulnerability of cancer cells is not clear. However, we show here that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer (TNBC). Using a high-throughput imaging-based reporter drug screen with 9 501 compounds, we have identified three polo-like kinase 1 (PLK1) inhibitors as major inducers of ERα protein expression and downstream activity in TNBC cells. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest, and ultimately cell death. Furthermore, 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, the upregulation of genes upon PLK1 inhibition correlates with their expression in normal breast tissue and with better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition is a potential alternative strategy to treat TNBC.
(© 2022. The Author(s).)
Databáze: MEDLINE
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