A Prospective Tumour Marker for Breast Cancer: YWHAB and Its Role in Promoting Oncogenic Phenotypes

Overview

Journal Breast Cancer (Dove Med Press)

Publisher Dove Medical Press

Date 2024 Dec 20

PMID 39703345

Authors

Vaishnavi L Gopaul

Lacey Winstone

Beatrice G Gatien

Braydon D Nault

Sujit Maiti

Reid M Opperman

Mousumi Majumder

Affiliations

Soon will be listed here.

Abstract

Background: YWHAB (14-3-3 Beta) was found in the secretome of miR-526b and miR-655 overexpressed breast cancer (BRCA) cell lines. The potential of YWHAB as a therapeutic target or biomarker for BRCA is investigated here.

Methods: After YWHAB was knocked down with siRNA, BRCA cell lines were used for in vitro assays (proliferation, migration, epithelial-to-mesenchymal transition). In silico analysis and in situ validation with BRCA plasma and biopsy tissues were used to test YWHAB's biomarker potential.

Results: YWHAB RNA and protein expression are elevated in aggressive BRCA cell lines, and the knockdown of YWHAB inhibited cell migration, proliferation, and EMT in all subtypes of tumour cell lines. YWHAB expression is significantly higher in BRCA biopsy tissue and blood plasma compared to control tissues and benign plasmas. YWHAB is expressed in all hormonal subtypes of BRCA tumours and has shown increased expression in advanced tumour stages. Its high expression is linked to poor patient survival. YWHAB is a sensitivity tumour marker (AUC of 0.7340, p = 0.0012) but is not a promising blood biomarker. Nevertheless, combined with pri-miR-526b, YWHAB mRNA expression shows potential as a BRCA blood biomarker (AUC of 0.711, p = 0.032), which must be validated in a larger sample set.

Conclusion: We elucidate the novel role of YWHAB as a therapeutic target in BRCA, given that its inhibition mitigated aggressive phenotypes across all tumour subtypes, including triple-negative breast cancer. Furthermore, emerges as a potential tumour marker, exhibiting high expression in metastatic BRCA and correlating with poor patient survival; however, it is not a sensitive blood biomarker.

References

Xu C, Du Z, Ren S, Liang X, Li H . MiR-129-5p sensitization of lung cancer cells to etoposide-induced apoptosis by reducing YWHAB. J Cancer. 2020; 11(4):858-866. PMC: 6959023. DOI: 10.7150/jca.35410. View

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

van Hemert M, Steensma H, van Heusden G . 14-3-3 proteins: key regulators of cell division, signalling and apoptosis. Bioessays. 2001; 23(10):936-46. DOI: 10.1002/bies.1134. View

Lai H, Li Y, Zhang H, Hu J, Liao J, Su Y . exoRBase 2.0: an atlas of mRNA, lncRNA and circRNA in extracellular vesicles from human biofluids. Nucleic Acids Res. 2021; 50(D1):D118-D128. PMC: 8728150. DOI: 10.1093/nar/gkab1085. View

Tseng C, Yang J, Chen C, Huang H, Chuang K, Lin C . Identification of 14-3-3β in human gastric cancer cells and its potency as a diagnostic and prognostic biomarker. Proteomics. 2011; 11(12):2423-39. DOI: 10.1002/pmic.201000449. View

Freeman A, Morrison D . 14-3-3 Proteins: diverse functions in cell proliferation and cancer progression. Semin Cell Dev Biol. 2011; 22(7):681-7. PMC: 3221730. DOI: 10.1016/j.semcdb.2011.08.009. View

Feser R, Opperman R, Nault B, Maiti S, Chen V, Majumder M . Breast cancer cell secretome analysis to decipher miRNA regulating the tumor microenvironment and discover potential biomarkers. Heliyon. 2023; 9(4):e15421. PMC: 10148110. DOI: 10.1016/j.heliyon.2023.e15421. View

Chen E, Tan C, Kou Y, Duan Q, Wang Z, Meirelles G . Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013; 14:128. PMC: 3637064. DOI: 10.1186/1471-2105-14-128. View

Shin B, Feser R, Nault B, Hunter S, Maiti S, Ugwuagbo K . miR526b and miR655 Induce Oxidative Stress in Breast Cancer. Int J Mol Sci. 2019; 20(16). PMC: 6720387. DOI: 10.3390/ijms20164039. View

10.

Sauerbrei W, Taube S, McShane L, Cavenagh M, Altman D . Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): An Abridged Explanation and Elaboration. J Natl Cancer Inst. 2018; 110(8):803-811. PMC: 6093349. DOI: 10.1093/jnci/djy088. View

11.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

12.

Tang Z, Kang B, Li C, Chen T, Zhang Z . GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019; 47(W1):W556-W560. PMC: 6602440. DOI: 10.1093/nar/gkz430. View

13.

Yang X, Wang J, Guo S, Fan K, Li J, Wang Y . miR-21 promotes keratinocyte migration and re-epithelialization during wound healing. Int J Biol Sci. 2011; 7(5):685-90. PMC: 3107477. DOI: 10.7150/ijbs.7.685. View

14.

Zhang X, Zhang Q, Zhang K, Wang F, Qiao X, Cui J . Circ SMARCA5 Inhibited Tumor Metastasis by Interacting with SND1 and Downregulating the YWHAB Gene in Cervical Cancer. Cell Transplant. 2021; 30:963689720983786. PMC: 7894587. DOI: 10.1177/0963689720983786. View

15.

Foote M, Zhou Y . 14-3-3 proteins in neurological disorders. Int J Biochem Mol Biol. 2012; 3(2):152-64. PMC: 3388734. View

16.

Berghuis A, Koffijberg H, Prakash J, Terstappen L, IJzerman M . Detecting Blood-Based Biomarkers in Metastatic Breast Cancer: A Systematic Review of Their Current Status and Clinical Utility. Int J Mol Sci. 2017; 18(2). PMC: 5343898. DOI: 10.3390/ijms18020363. View

17.

Cerami E, Gao J, Dogrusoz U, Gross B, Sumer S, Aksoy B . The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2(5):401-4. PMC: 3956037. DOI: 10.1158/2159-8290.CD-12-0095. View

18.

Hunter S, Nault B, Ugwuagbo K, Maiti S, Majumder M . Mir526b and Mir655 Promote Tumour Associated Angiogenesis and Lymphangiogenesis in Breast Cancer. Cancers (Basel). 2019; 11(7). PMC: 6678879. DOI: 10.3390/cancers11070938. View

19.

Aitken A . 14-3-3 proteins: a historic overview. Semin Cancer Biol. 2006; 16(3):162-72. DOI: 10.1016/j.semcancer.2006.03.005. View

20.

Majumder M, Dunn L, Liu L, Hasan A, Vincent K, Brackstone M . COX-2 induces oncogenic micro RNA miR655 in human breast cancer. Sci Rep. 2018; 8(1):327. PMC: 5762661. DOI: 10.1038/s41598-017-18612-3. View