TY - JOUR
T1 - CRYβB2 enhances tumorigenesis through upregulation of nucleolin in triple negative breast cancer
AU - Yan, Yu
AU - Narayan, Athira
AU - Cho, Soonweng
AU - Cheng, Zhiqiang
AU - Liu, Jun O.
AU - Zhu, Heng
AU - Wang, Guannan
AU - Wharram, Bryan
AU - Lisok, Ala
AU - Brummet, Mary
AU - Saeki, Harumi
AU - Huang, Tao
AU - Gabrielson, Kathleen
AU - Gabrielson, Edward
AU - Cope, Leslie
AU - Kanaan, Yasmine M.
AU - Afsari, Ali
AU - Naab, Tammey
AU - Yfantis, Harris G.
AU - Ambs, Stefan
AU - Pomper, Martin G.
AU - Sukumar, Saraswati
AU - Merino, Vanessa F.
N1 - Funding Information:
This work was funded by the DOD BCRP Center of Excellence Grant W81XWH-04-1-0595 to S.S, DOD BCRP, W81XWH-15-1-0017 to V.M and the Division of Nuclear Medicine and Molecular Imaging.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/9/23
Y1 - 2021/9/23
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-021-01975-3
DO - 10.1038/s41388-021-01975-3
M3 - Article
C2 - 34341513
AN - SCOPUS:85111822624
SN - 0950-9232
VL - 40
SP - 5752
EP - 5763
JO - Oncogene
JF - Oncogene
IS - 38
ER -