CRYβB2 enhances tumorigenesis through upregulation of nucleolin in triple negative breast cancer

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.