CRYβB2 enhances tumorigenesis through upregulation of nucleolin in triple negative breast cancer.
Animals
Aptamers, Nucleotide
/ administration & dosage
Cell Nucleolus
/ drug effects
Cell Proliferation
/ drug effects
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice
Neoplasm Invasiveness
Neoplasm Transplantation
Neoplastic Stem Cells
/ drug effects
Oligodeoxyribonucleotides
/ administration & dosage
Phosphoproteins
/ metabolism
RNA-Binding Proteins
/ metabolism
Signal Transduction
/ drug effects
Triple Negative Breast Neoplasms
/ drug therapy
Up-Regulation
beta-Crystallin B Chain
/ genetics
Nucleolin
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
25
11
2020
accepted:
21
07
2021
revised:
13
07
2021
pubmed:
4
8
2021
medline:
31
12
2021
entrez:
3
8
2021
Statut:
ppublish
Résumé
Expression of β-crystallin B2 (CRYβB2) is elevated in African American (AA) breast tumors. The underlying mechanisms of CRYβB2-induced malignancy and the association of CRYβB2 protein expression with survival have not yet been described. Here, we report that the expression of CRYβB2 in breast cancer cells increases stemness, growth, and metastasis. Transcriptomics data revealed that CRYβB2 upregulates genes that are functionally associated with unfolded protein response, oxidative phosphorylation, and DNA repair, while down-regulating genes related to apoptosis. CRYβB2 in tumors promotes de-differentiation, an increase in mesenchymal markers and cancer-associated fibroblasts, and enlargement of nucleoli. Proteome microarrays identified a direct interaction between CRYβB2 and the nucleolar protein, nucleolin. CRYβB2 induces nucleolin, leading to the activation of AKT and EGFR signaling. CRISPR studies revealed a dependency on nucleolin for the pro-tumorigenic effects of CRYβB2. Triple-negative breast cancer (TNBC) xenografts with upregulated CRYβB2 are distinctively sensitive to the nucleolin aptamer, AS-1411. Lastly, in AA patients, higher levels of nucleolar CRYβB2 in primary TNBC correlates with decreased survival. In summary, CRYβB2 is upregulated in breast tumors of AA patients and induces oncogenic alterations consistent with an aggressive cancer phenotype. CRYβB2 increases sensitivity to nucleolin inhibitors and may promote breast cancer disparity.
Identifiants
pubmed: 34341513
doi: 10.1038/s41388-021-01975-3
pii: 10.1038/s41388-021-01975-3
pmc: PMC10064491
mid: NIHMS1879574
doi:
Substances chimiques
AGRO 100
0
Aptamers, Nucleotide
0
Oligodeoxyribonucleotides
0
Phosphoproteins
0
RNA-Binding Proteins
0
beta-Crystallin B Chain
0
beta-crystallin B2
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5752-5763Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC010887
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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