Targeting PML in triple negative breast cancer elicits growth suppression and senescence
| Autor: | Ivana Hermanova, Rosa Barrio, Sara Fernández, Villanueva J, Marco Piva, Miquel Angel Pujana, Laura Bozal-Basterra, Ana R. Cortazar, Andrea Alimonti, Patricia Zúñiga-García, Ariane Schaub-Clerigué, Amaia Zabala-Letona, Ianire Astobiza, Amaia Arruabarrena-Aristorena, James D. Sutherland, Canals F, Lorea Valcarcel-Jimenez, Crespo, Ajinkya Revandkar, Leire Arreal, Torrano, Arkaitz Carracedo, Natalia Martín-Martín |
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| Přispěvatelé: | European Commission |
| Rok vydání: | 2020 |
| Předmět: |
Senescence
tumors senescence P27(KIP1) medicine.medical_treatment PIM1 Triple Negative Breast Neoplasms pathway activation MYC fatty-acid oxidation Promyelocytic Leukemia Protein Biology Article Targeted therapy nhibits cell-proliferation Proto-Oncogene Proteins c-myc Mice 03 medical and health sciences Promyelocytic leukemia protein breast cancer 0302 clinical medicine Proto-Oncogene Proteins c-pim-1 Cell Line Tumor oncogene addition medicine Animals Humans Gene Silencing Nuclear protein Molecular Biology Cellular Senescence Triple-negative breast cancer Cell Proliferation 030304 developmental biology 0303 health sciences therapy P53 PML Oncogene p27 Cell Biology Oncogene Addiction 3. Good health 030220 oncology & carcinogenesis Cancer research biology.protein Cyclin-Dependent Kinase Inhibitor p27 |
| Zdroj: | Addi. Archivo Digital para la Docencia y la Investigación instname Cell Death and Differentiation, 27 (4) Cell death and differentiation |
| Popis: | 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. Aologies to those whose related publications were not cited due to space limitations. LA, AS, MPu, AA-A, and LV-J were supported by the Basque Government of education. IH was supported by the Program "Juan de la Cierva" from MINECO. FC acknowledges the Proteomics Unit at VHIO is a member ProteoRed, PRB3 (Grant IPT17/0019-ISCIII-SGEFI/ERDF. RB acknowledges projects BFU2017-84653-P, Consolider BFU2014-57703-REDC, and SAF2017-90900-REDT (MINECO/FEDER, EU). The work of VT is founded by Fundacion Vasca de Innovacion e Investigacion Sanitarias, BIOEF (BIO15/CA/052), the AECC J.P. Bizkaia, the Basque Department of Health (2016111109) and the MINECO (RTI2018-097267-B-I00 (MCIU/AEI/FEDER, UE)). AA was supported by ERC consolidator (683136) and Swiss Cancer League (KFS4267-08-2017) grant, Dr. Josef Steiner Foundation, Swiss CardOnco-Grant of Alfred and Annemarie von Sick grant, Helmut Horten Foundation, SNSF (310030_176045) and PCUK (RIA15-ST2-018). NM-M was supported by the Spanish Association Against Cancer (AECC), AECC JP Vizcaya and CIBERONC. The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and the department of education (IKERTALDE IT1106-16), the BBVA foundation, the MINECO (SAF2016-79381R (FEDER/EU); Severo Ochoa Excellence Accreditation SEV2016-0644; Excellence Networks SAF2016-81975-REDT), European Training Networks Project (H2020-MSCA-ITN-308 2016 721532), the AECC (IDEAS175CARR, GCTRA18006CARR), La Caixa Foundation (HR17-00094), FERO foundation, the AstraZeneca Oncology prize and the European Research Council (Starting Grant 336343, PoC 754627). CIBERONC was co-funded with FEDER funds and funded by ISCIII. |
| Databáze: | OpenAIRE |
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