Targeting PML in triple negative breast cancer elicits growth suppression and senescence.

Animals Cell Line, Tumor Cell Proliferation Cellular Senescence Cyclin-Dependent Kinase Inhibitor p27 / metabolism Gene Silencing Humans Mice Promyelocytic Leukemia Protein / metabolism Proto-Oncogene Proteins c-myc / metabolism Proto-Oncogene Proteins c-pim-1 / metabolism Triple Negative Breast Neoplasms / metabolism

Journal

Cell death and differentiation

ISSN: 1476-5403

Titre abrégé: Cell Death Differ

Pays: England

ID NLM: 9437445

Informations de publication

Date de publication:
04 2020

Historique:

received: 24 11 2018

accepted: 23 07 2019

revised: 18 07 2019

pubmed: 2 10 2019

medline: 30 6 2021

entrez: 2 10 2019

Statut: ppublish

Résumé

Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.

Identifiants

DOI: 10.1038/s41418-019-0407-5 PMID: 31570853 PMC: PMC7104349

pubmed: 31570853

doi: 10.1038/s41418-019-0407-5

pii: 10.1038/s41418-019-0407-5

pmc: PMC7104349

mid: EMS83797

doi:

Substances chimiques

Promyelocytic Leukemia Protein 0

Proto-Oncogene Proteins c-myc 0

Cyclin-Dependent Kinase Inhibitor p27 147604-94-2

PIM1 protein, human EC 2.7.11.1

Proto-Oncogene Proteins c-pim-1 EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1186-1199

Subventions

Organisme : European Research Council

ID : 336343

Pays : International

Organisme : European Research Council

ID : 683136

Pays : International

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