期刊
ONCOGENE
卷 40, 期 38, 页码 5752-5763出版社
SPRINGERNATURE
DOI: 10.1038/s41388-021-01975-3
关键词
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资金
- DOD BCRP Center of Excellence Grant [W81XWH-04-1-0595]
- DOD BCRP [W81XWH-15-1-0017]
- Division of Nuclear Medicine and Molecular Imaging
CRY beta B2 is upregulated in breast tumors of African American patients, leading to malignancy and decreased survival. This protein enhances the stemness and metastatic properties of breast cancer cells by activating multiple signaling pathways.
Expression of beta-crystallin B2 (CRY beta B2) is elevated in African American (AA) breast tumors. The underlying mechanisms of CRY beta B2-induced malignancy and the association of CRY beta B2 protein expression with survival have not yet been described. Here, we report that the expression of CRY beta B2 in breast cancer cells increases stemness, growth, and metastasis. Transcriptomics data revealed that CRY beta B2 upregulates genes that are functionally associated with unfolded protein response, oxidative phosphorylation, and DNA repair, while down-regulating genes related to apoptosis. CRY beta B2 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 CRY beta B2 and the nucleolar protein, nucleolin. CRY beta B2 induces nucleolin, leading to the activation of AKT and EGFR signaling. CRISPR studies revealed a dependency on nucleolin for the pro-tumorigenic effects of CRY beta B2. Triple-negative breast cancer (TNBC) xenografts with upregulated CRY beta B2 are distinctively sensitive to the nucleolin aptamer, AS-1411. Lastly, in AA patients, higher levels of nucleolar CRY beta B2 in primary TNBC correlates with decreased survival. In summary, CRY beta B2 is upregulated in breast tumors of AA patients and induces oncogenic alterations consistent with an aggressive cancer phenotype. CRY beta B2 increases sensitivity to nucleolin inhibitors and may promote breast cancer disparity.
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