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

Oncogene volume 40, pages 5752–5763 (2021)Cite this article

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Abstract

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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Fig. 1: CRYβB2 is overexpressed in AA tumors and promotes tumorigenesis.
Fig. 2: CRYβB2 tumors present features of aggressive breast cancer.
Fig. 3: CRYβB2 interactome and regulation of translation.
Fig. 4: CRYβB2 associates to nucleolin and regulate its pathway.
Fig. 5: CRYβB2 tumorigenesis is targeted by nucleolin inhibitors.
Fig. 6: CRYβB2 associates with poor TNBC outcome in AA women.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yu Yan, Athira Narayan, Bryan Wharram, Ala Lisok, Mary Brummet, Martin G. Pomper & Vanessa F. Merino

  2. Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yu Yan & Tao Huang

  3. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yu Yan, Soonweng Cho, Jun O. Liu, Guannan Wang, Kathleen Gabrielson, Leslie Cope, Martin G. Pomper & Saraswati Sukumar

  4. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Zhiqiang Cheng, Jun O. Liu, Heng Zhu & Martin G. Pomper

  5. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Harumi Saeki & Kathleen Gabrielson

  6. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Harumi Saeki, Kathleen Gabrielson & Edward Gabrielson

  7. Department of Microbiology, College of Medicine, Howard University, Washington, DC, USA

    Yasmine M. Kanaan

  8. Department of Pathology, College of Medicine, Howard University, Washington, DC, USA

    Ali Afsari & Tammey Naab

  9. Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA

    Harris G. Yfantis

  10. Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Stefan Ambs

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Contributions

Conception and experimental design: Y.Y., V.M. and S.S. Performed the experiments: Y.Y., A.N., V.M., S.C., Z.C., G.W., B.W., A.L., M.B., H.S. and H.Y., Acquisition of data: V.M., S.C., J.L., H. Z., T.H., K.G., L.C., E.G. and S.S. Analysis and interpretation of data: V.M., S.C., L.C., J.L., H.Z., K.G., S.A., M.P. and S.S. Writing and/or revision of the manuscript: Y.Y., S.A., V.M., M.P. and S.S. Study supervision: V.M., M.P. and S.S. GEO accession number: GSE137916.

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Correspondence to Saraswati Sukumar or Vanessa F. Merino.

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Yan, Y., Narayan, A., Cho, S. et al. CRYβB2 enhances tumorigenesis through upregulation of nucleolin in triple negative breast cancer. Oncogene 40, 5752–5763 (2021). https://doi.org/10.1038/s41388-021-01975-3

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