Lineage-specific mechanisms and drivers of breast cancer chemoresistance revealed by 3D biomimetic culture.
3D models
DNA repair
breast cancer
doxorubicin
drug resistance
lysosomes
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
17
05
2021
received:
06
10
2020
accepted:
08
06
2021
pubmed:
11
6
2021
medline:
8
4
2022
entrez:
10
6
2021
Statut:
ppublish
Résumé
To improve the success rate of current preclinical drug trials, there is a growing need for more complex and relevant models that can help predict clinical resistance to anticancer agents. Here, we present a three-dimensional (3D) technology, based on biomimetic collagen scaffolds, that enables the modeling of the tumor hypoxic state and the prediction of in vivo chemotherapy responses in terms of efficacy, molecular alterations, and emergence of resistance mechanisms. The human breast cancer cell lines MDA-MB-231 (triple negative) and MCF-7 (luminal A) were treated with scaling doses of doxorubicin in monolayer cultures, 3D collagen scaffolds, or orthotopically transplanted murine models. Lineage-specific resistance mechanisms were revealed by the 3D tumor model. Reduced drug uptake, increased drug efflux, and drug lysosomal confinement were observed in triple-negative MDA-MB-231 cells. In luminal A MCF-7 cells, the selection of a drug-resistant subline from parental cells with deregulation of p53 pathways occurred. These cells were demonstrated to be insensitive to DNA damage. Transcriptome analysis was carried out to identify differentially expressed genes (DEGs) in treated cells. DEG evaluation in breast cancer patients demonstrated their potential role as predictive biomarkers. High expression of the transporter associated with antigen processing 1 (TAP1) and the tumor protein p53-inducible protein 3 (TP53I3) was associated with shorter relapse in patients affected by ER
Identifiants
pubmed: 34109737
doi: 10.1002/1878-0261.13037
pmc: PMC8847989
doi:
Substances chimiques
Doxorubicin
80168379AG
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
921-939Informations de copyright
© 2021 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
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