BCL6 and the Notch pathway: a signaling axis leading to a novel druggable biotarget in triple negative breast cancer.

Autor: De Santis F; Unit of Immunotherapy and Anticancer Innovative Therapeutics, Department of Medical Oncology and Hematology Fondazione, IRCCS Istituto Nazionale Dei Tumori, Milan, Italy., Romero-Cordoba SL; Department of Genomic Medicine and Toxicology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.; Biochemistry Department, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Mexico City, Mexico., Castagnoli L; Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy., Volpari T; The New York Stem Cell Foundation Research Institute, New York, NY, USA., Faraci S; Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy., Fucà G; Unit of Immunotherapy and Anticancer Innovative Therapeutics, Department of Medical Oncology and Hematology Fondazione, IRCCS Istituto Nazionale Dei Tumori, Milan, Italy., Tagliabue E; Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy., De Braud F; Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.; Department of Oncology and Oncohematology, University of Milan, Milan, Italy., Pupa SM; Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy., Di Nicola M; Unit of Immunotherapy and Anticancer Innovative Therapeutics, Department of Medical Oncology and Hematology Fondazione, IRCCS Istituto Nazionale Dei Tumori, Milan, Italy. massimo.dinicola@istitutotumori.mi.it.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2022 Apr; Vol. 45 (2), pp. 257-274. Date of Electronic Publication: 2022 Mar 31.
DOI: 10.1007/s13402-022-00663-y
Abstrakt: Background: The transcriptional repressor B-cell lymphoma 6 (BCL6) is dysregulated in several neoplasms, but its role in triple negative breast cancer (TNBC), a highly aggressive subtype which lacks effective treatment, is unclear. The presence of intratumoral cancer stem cells (CSCs) is a main cause of tumor relapse. The Notch signaling pathway is crucial for regulating CSC self-renewal and promoting breast cancer (BC) development and resistance to anticancer therapies. Here, we investigated signaling cascades of BCL6 in the CSC compartment of TNBCs, and the mechanisms that govern its activity, mainly through Notch signaling.
Methods: Gene expression, somatic copy number alterations and clinical data from the Cancer Genome Atlas and METABRIC were accessed through the Xena and cbioportal browsers. Public transcriptome profiles from TNBC datasets were retrieved from the Gene Expression Omnibus. Mammosphere formation efficiency was calculated after BCL6 knockdown via transient siRNA transfection, stable silencing or pharmacological inhibition. The effects exhibited via BCL6 inhibition in putative TNBC stem-like cells were evaluated by immunofluorescence and qRT-PCR analyses. Chromatin immunoprecipitation experiments were performed to validate a putative BCL6 responsive element located in the first intron of the Numb gene and to define the circuit of corepressors engaged by BCL6 following its inhibition. Immunoprecipitation assays were carried out to investigate a novel interaction at the basis of BCL6 control of CSC activity in TNBC.
Results: In silico analyses of benchmarked public datasets revealed a significant enrichment of BCL6 in cancer stemness related pathways, particularly of Notch signaling in TNBC. In vitro stable inhibition of BCL6 significantly reduced tumor cell growth and, accordingly, we found that the mammosphere formation efficiency of BCL6 silenced cells was significantly impaired by pharmacological inhibition of Notch signaling. BCL6 was found to be expressed at significantly higher levels in TNBC mammospheres than in their adherent counterparts, and loss of BCL6 function significantly decreased mammosphere formation with preferential targeting of CD44-positive versus ALDH-positive stem-like cells. Functional interplay between BCL6 and the chromatin remodeling factor EZH2 triggered the BCL6/Notch stemness signaling axis via inhibition of Numb transcription.
Conclusions: Our results may be instrumental for the prospective design of combination treatment strategies that selectively target novel TNBC-associated biomarker(s) whose activity is implicated in the regulation of cancer stemness (such as BCL6) and molecules in developmentally conserved signaling pathways (such as Notch) to achieve long-lasting tumor control and improve patient outcomes.
(© 2022. Springer Nature Switzerland AG.)
Databáze: MEDLINE
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