Association of ZWINT Expression with Clinicopathologic Characteristics and Prognosis in Breast Cancer Patients

Abstract

Objective

ZW10 interacting kinetochore protein (ZWINT) has been demonstrated to play a pivotal role in the growth, invasion, and migration of cancers. Nevertheless, whether the expression levels of ZWINT are significantly correlated with clinicopathological characteristics and prognostic outcomes of patients with breast cancer remains elusive. This study systematically investigated the clinical significance of ZWINT expression in breast cancer through integrated molecular subtyping and survival analysis.

Methods

We systematically characterized the spatial expression pattern of ZWINT across various breast cancer subtypes and assessed its prognostic significance using an integrated bioinformatics approach that involved multi-omics analysis. The approach included the Breast Cancer Gene-Expression Miner v5.1 (bc-GenExMiner v5.1), TNMplot, MuTarget, PrognoScan database, and Database for Annotation, Visualization, and Integrated Discovery (DAVID).

Results

Our analysis revealed consistent upregulation of ZWINT mRNA and protein expression across distinct clinicopathological subtypes of breast cancer. ZWINT overexpression demonstrated significant co-occurrence with truncating mutations in cadherin 1 (CDH1) and tumor protein p53 (TP53), suggesting potential functional crosstalk in tumor progression pathways. The overexpression of ZWINT correlated with adverse clinical outcomes, showing 48% increased mortality risk (overall survival: HR 1.48, 95% CI 1.23–1.79), 66% higher recurrence probability (relapse-free survival: 1.66, 95% CI 1.50–1.84), and 63% elevated metastasis risk (distant metastasis-free survival: HR 1.63, 95% CI 1.39–1.90). Multivariate Cox regression incorporating TNM staging and molecular subtypes confirmed ZWINT as an independent prognostic determinant (P < 0.001, Harrell’s C-index = 0.7827), which was validated through bootstrap resampling (1000 iterations).

Conclusion

ZWINT may serve as a potential biomarker for prognosis and a possible therapeutic target alongside TP53/CDH1 in breast cancer.

Keywords

ZW10 interacting kinetochore protein (ZWINT) / Breast cancer / Prognosis / Public databases / Prognostic value / Comprehensive analysis

References

[1] SiegelRL, MillerKD, WagleNS, et al.. Cancer statistics, 2023. CA Cancer J Clin., 2023, 73(1): 17-48

[2] WaksAG, WinerEP. Breast cancer treatment: a review. JAMA., 2019, 321(3): 288-300.

[3] Krystel-WhittemoreM, TanPH, WenHY. Predictive and prognostic biomarkers in breast tumours. Pathology., 2024, 56(2): 186-191.

[4] StarrDA, SafferyR, LiZ, et al.. HZwint-1, a novel human kinetochore component that interacts with HZW10. J Cell Sci., 2000, 113(Pt 11): 1939-1950.

[5] PengF, LiQ, NiuSQ, et al.. ZWINT is the next potential target for lung cancer therapy. J Cancer Res Clin Oncol., 2019, 145(3): 661-673.

[6] MaZ, CaiY, TianC. ZWINT promotes the proliferation, migration, and invasion of cervical cancer cells by regulating the p53/p21 signaling pathway. Chin J Physiol., 2023, 66(5): 372-378.

[7] YangL, HanN, ZhangX, et al.. ZWINT: A potential therapeutic biomarker in patients with glioblastoma correlates with cell proliferation and invasion. Oncol Rep., 2020, 43(6): 1831-1844

[8] TangZ, LiC, KangB, et al.. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res., 2017, 45(W1): W98-W102.

[9] RiggioAI, VarleyKE, WelmAL. The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer., 2021, 124(1): 13-26.

[10] ShuY, PangX, LiH, et al.. A multidimensional analysis of ZW10 interacting kinetochore protein in human tumors. Am J Cancer Res., 2024, 14(1): 390-402.

[11] ShaoMT, HuYZ, DingH, et al.. The overexpression of ZWINT in integrated bioinformatics analysis forecasts poor prognosis in breast cancer. Transl Cancer Res., 2020, 9(1): 187-193.

[12] KhanB, QahwajiR, AlfaifiMS, et al.. Deciphering molecular landscape of breast cancer progression and insights from functional genomics and therapeutic explorations followed by in vitro validation. Sci Rep., 2024, 14128794.

[13] YingH, XuZ, ChenM, et al.. Overexpression of Zwint predicts poor prognosis and promotes the proliferation of hepatocellular carcinoma by regulating cell-cycle-related proteins. Onco Targets Ther., 2018, 11: 689-702.

[14] WangB, WangW, WangH, et al.. Microarray Analysis of Novel Genes Involved in Nasopharyngeal Carcinoma. Bull Exp Biol Med., 2021, 170(5): 658-664.

[15] LiW, FengSS, WuH, et al.. Comprehensive Analysis of CDK1-Associated ceRNA Network Revealing the Key Pathways LINC00460/LINC00525-Hsa-Mir-338-FAM111/ZWINT as Prognostic Biomarkers in Lung Adenocarcinoma Combined with Experiments. Cells., 2022, 1171220.

[16] ElorantaS, BomanM. Predictive models for clinical decision making: deep dives in practical machine learning. J Intern Med., 2022, 292(2): 278-295.

[17] EbringC, MarlinR, MacniJ, et al.. Type II endometrial cancer: Incidence, overall and disease-free survival in Martinique. PLoS One., 2023, 183. e0278757

[18] NagyA, GyorffyB. muTarget: a platform linking gene expression changes and mutation status in solid tumors. Int J Cancer., 2021, 148(2): 502-511.

[19] BoettcherS, MillerPG, SharmaR, et al.. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science., 2019, 365(6453): 599-604.

[20] DaverNG, MaitiA, KadiaTM, et al.. TP53-mutated myelodysplastic syndrome and acute myeloid leukemia: biology, current therapy, and future directions. Cancer Discov., 2022, 12(11): 2516-2529.

[21] ShahbandiA, NguyenHD, JacksonJG. TP53 mutations and outcomes in breast cancer: reading beyond the headlines. Trends Cancer., 2020, 6(2): 98-110.

[22] SchonK, TischkowitzM. Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat., 2018, 167(2): 417-423.

[23] GirardiA, MagnoniF, ViciniE, et al.. CDH1 germline mutations in families with hereditary lobular breast cancer. Eur J Cancer Prev., 2022, 31(3): 274-278.

[24] DjerroudiL, BendaliA, FuhrmannL, et al.. E-cadherin mutational landscape and outcomes in breast invasive lobular carcinoma. Mod Pathol., 2024, 3710100570.

Funding

Maternal and Child Health Hospital of Hubei Province Research Project(2023SFYM008)

Key Project of Hubei Provincial Natural Science Foundation(JCZRLH202500304)

RIGHTS & PERMISSIONS

The Author(s)