as-1411 and Triple-Negative-Breast-Neoplasms

Targeted lipid nanobubbles as theranostic ultrasound molecular probes with both targeted contrast-enhanced ultrasound molecular imaging and synergistic treatment capabilities are expected to overcome severe challenges in the diagnosis and treatment of refractory triple-negative breast cancer (TNBC). In this study, AS1411 aptamer-functionalised nucleolin-targeted doxorubicin-loaded lipid nanobubbles (AS1411-DOX-NBs) were constructed, and their physicochemical properties as well as anti-tumour and cardioprotective efficacies were systematically tested and evaluated. The results showed that AS1411-DOX-NBs can carry and maintain the physicochemical and pharmacodynamic properties of doxorubicin (DOX) and show stronger tumour cell-killing ability

Topics: Animals; Aptamers, Nucleotide; Cardiotonic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Doxorubicin; Echocardiography; Female; Humans; Liposomes; Mice; Nanoparticles; Nanostructures; Nucleolin; Oligodeoxyribonucleotides; Phosphoproteins; RNA-Binding Proteins; Treatment Outcome; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

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.

Topics: Animals; Aptamers, Nucleotide; beta-Crystallin B Chain; Cell Nucleolus; Cell Proliferation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Invasiveness; Neoplasm Transplantation; Neoplastic Stem Cells; Nucleolin; Oligodeoxyribonucleotides; Phosphoproteins; RNA-Binding Proteins; Signal Transduction; Triple Negative Breast Neoplasms; Up-Regulation