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STK3 higher expression association with clinical characteristics in intrinsic subtypes of breast cancer invasive ductal carcinoma patients

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Abstract

Purpose

STK3 has a central role in maintaining cell homeostasis, proliferation, growth, and apoptosis. Previously, we investigated the functional link between STK3/MST2, and estrogen receptor in MCF-7 breast cancer cells. To expand the investigation, this study evaluated STK3’s higher expression and associated genes in breast cancer intrinsic subtypes using publicly available data.

Methods

The relationship between clinical pathologic features and STK3 high expression was analyzed using descriptive and multivariate analysis.

Results

Increased STK3 expression in breast cancer was significantly associated with higher pathological cancer stages, and a different expression level was observed in the intrinsic subtypes of breast cancer. Kaplan–Meier analysis showed that breast cancer with high STK3 had a lower survival rate in IDC patients than that with low STK3 expression (p < 0.05). The multivariate analysis unveiled a strong correlation between STK3 expression and the survival rate among IDC patients, demonstrating hazard ratios for lower expression. In the TCGA dataset, the hazard ratio was 0.56 (95% CI 0.34–0.94, p = 0.029) for patients deceased with tumor, and 0.62 (95% CI 0.42–0.92, p = 0.017) for all deceased patients. Additionally, in the METABRIC dataset, the hazard ratio was 0.76 (95% CI 0.64–0.91, p = 0.003) for those deceased with tumor. From GSEA outcomes 7 gene sets were selected based on statistical significance (FDR < 0.25 and p < 0.05). Weighted Sum model (WSM) derived top 5% genes also have higher expression in basal and lower in luminal A in association with STK3.

Conclusion

By introducing a novel bioinformatics approach that combines GSEA and WSM, the study successfully identified the top 5% of genes associated with higher expression of STK3.

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Data availability

The data used in this study is openly accessible and can be found at https://www.cbioportal.org/datasets. Specifically, the following datasets were employed: (1) Breast Invasive Carcinoma (TCGA, PanCancer Atlas 2018). (2) Breast Cancer (METABRIC, Nature 2012 & Nat Commun 2016).

References

  1. Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, Ji X, Liu W, Huang B, Luo W, Liu B, Lei Y, Du S, Vuppalapati A, Luu HH, Haydon RC, He TC, Ren G (2018) Breast cancer development and progression: risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis 5:77–106. https://doi.org/10.1016/j.gendis.2018.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yu F, Quan F, Xu J, Zhang Y, Xie Y, Zhang J, Lan Y, Yuan H, Zhang H, Cheng S, Xiao Y, Li X (2019) Breast cancer prognosis signature: linking risk stratification to disease subtypes. Brief Bioinform 20:2130–2140. https://doi.org/10.1093/bib/bby073

    Article  CAS  PubMed  Google Scholar 

  3. Pan D (2010) The hippo signaling pathway in development and cancer. Dev Cell 19:491–505. https://doi.org/10.1016/j.devcel.2010.09.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Park Y, Park J, Lee Y, Lim W, Oh BC, Shin C, Kim W, Lee Y (2011) Mammalian MST2 kinase and human salvador activate and reduce estrogen receptor alpha in the absence of ligand. J Mol Med 89:181–191. https://doi.org/10.1007/s00109-010-0698-y

    Article  CAS  PubMed  Google Scholar 

  5. Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY, Shi W, Jiang J, Yao PP, Zhu HP (2017) Risk factors and preventions of breast cancer. Int J Biol Sci 13:1387–1397. https://doi.org/10.7150/ijbs.21635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wu L, Yang X (2018) Targeting the hippo pathway for breast cancer therapy. Cancers (Basel). https://doi.org/10.3390/cancers10110422

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zheng Y, Pan D (2019) The Hippo signaling pathway in development and disease. Dev Cell 50:264–282. https://doi.org/10.1016/j.devcel.2019.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, Gayyed MF, Anders RA, Maitra A, Pan D (2007) Elucidation of a universal size-control mechanism in drosophila and mammals. Cell 130:1120–1133. https://doi.org/10.1016/j.cell.2007.07.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fallahi E, O’Driscoll NA, Matallanas D (2016) The MST/hippo pathway and cell death: a non-canonical affair. Genes 7:28

    Article  PubMed  PubMed Central  Google Scholar 

  10. Oka T, Mazack V, Sudol M (2008) Mst2 and lats kinases regulate apoptotic function of yes kinase-associated protein (YAP)*. J Biol Chem 283:27534–27546. https://doi.org/10.1074/jbc.M804380200

    Article  CAS  PubMed  Google Scholar 

  11. Ni L, Li S, Yu J, Min J, Brautigam Chad A, Tomchick Diana R, Pan D, Luo X (2013) Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5. Structure 21:1757–1768. https://doi.org/10.1016/j.str.2013.07.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thompson BJ, Sahai E (2015) MST kinases in development and disease. J Cell Biol 210:871–882. https://doi.org/10.1083/jcb.201507005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao B, Lei QY, Guan KL (2008) The Hippo–YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol 20:638–646. https://doi.org/10.1016/j.ceb.2008.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Turunen SP, von Nandelstadh P, Öhman T, Gucciardo E, Seashore-Ludlow B, Martins B, Rantanen V, Li H, Höpfner K, Östling P, Varjosalo M, Lehti K (2019) FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis. Cell Death Differ 26:2577–2593. https://doi.org/10.1038/s41418-019-0321-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang Y, Li J, Gao Y, Luo Y, Luo H, Wang L, Yi Y, Yuan Z, Jim Xiao Z-X (2019) Hippo kinases regulate cell junctions to inhibit tumor metastasis in response to oxidative stress. Redox Biol 26:101233. https://doi.org/10.1016/j.redox.2019.101233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lin XY, Cai FF, Wang MH, Pan X, Wang F, Cai L, Cui RR, Chen S, Biskup E (2017) Mammalian sterile 20-like kinase 1 expression and its prognostic significance in patients with breast cancer. Oncol Lett 14:5457–5463. https://doi.org/10.3892/ol.2017.6852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550. https://doi.org/10.1073/pnas.0506580102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. McMillan SS, Kelly F, Sav A, Kendall E, King MA, Whitty JA, Wheeler AJ (2014) Using the nominal group technique: how to analyse across multiple groups. Health Serv Outcomes Res Method 14:92–108. https://doi.org/10.1007/s10742-014-0121-1

    Article  Google Scholar 

  19. Chen B, Chan WN, Mui CW, Liu X, Zhang J, Wang Y, Cheung AHK, Chan AKY, Chan RCK, Leung KT, Dong Y, Pan Y, Ke H, Liang L, Zhou Z, Wong CC, Wu WKK, Cheng ASL, Yu J, Lo KW, To KF, Kang W (2021) STK3 promotes gastric carcinogenesis by activating Ras-MAPK mediated cell cycle progression and serves as an independent prognostic biomarker. Mol Cancer 20:147. https://doi.org/10.1186/s12943-021-01451-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liberzon A, Birger C, Ghandi M, Jill P, Tamayo P, Jolla L, Jolla L (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Iny Stein T, Nudel R, Lieder I, Mazor Y, Kaplan S, Dahary D, Warshawsky D, Guan-Golan Y, Kohn A, Rappaport N, Safran MD (2016) Lancet, the genecards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinform 1.30.1-1.30.33

  22. Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov Jill P, Tamayo P (2015) The molecular signatures database hallmark gene set collection. Cell Syst 1:417–425. https://doi.org/10.1016/j.cels.2015.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cheng Q, Chang JT, Geradts J, Neckers LM, Haystead T, Spector NL, Lyerly HK (2012) Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer. Breast Cancer Res 14:R62. https://doi.org/10.1186/bcr3168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hou L, Chen M, Wang M, Cui X, Gao Y, Xing T, Li J, Deng S, Hu J, Yang H, Jiang J (2016) Systematic analyses of key genes and pathways in the development of invasive breast cancer. Gene 593:1–12. https://doi.org/10.1016/j.gene.2016.08.007

    Article  CAS  PubMed  Google Scholar 

  25. Issac MSM, Yousef E, Tahir MR, Gaboury LA (2019) MCM2, MCM4, and MCM6 in breast cancer: clinical utility in diagnosis and prognosis. Neoplasia 21:1015–1035. https://doi.org/10.1016/j.neo.2019.07.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Park S, Brugiolo M, Akerman M, Das S, Urbanski L, Geier A, Kesarwani AK, Fan M, Leclair N, Lin K-T, Hu L, Hua I, George J, Muthuswamy SK, Krainer AR, Anczuków O (2019) Differential functions of splicing factors in mammary transformation and breast cancer metastasis. Cell Rep 29:2672-2688.e2677. https://doi.org/10.1016/j.celrep.2019.10.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schirmer AU, Driver LM, Zhao MT, Wells CI, Pickett JE, O’Bryne SN, Eduful BJ, Yang X, Howard L, You S, Devi GR, DiGiovanni J, Freedland SJ, Chi JT, Drewry DH, Macias E (2022) Non-canonical role of hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther 30:485–500. https://doi.org/10.1016/j.ymthe.2021.08.029

    Article  CAS  PubMed  Google Scholar 

  28. Seidel C, Schagdarsurengin U, Blümke K, Würl P, Pfeifer GP, Hauptmann S, Taubert H, Dammann R (2007) Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma. Mol Carcinog 46:865–871. https://doi.org/10.1002/mc.20317

    Article  CAS  PubMed  Google Scholar 

  29. Wang X, Wang F, Zhang ZG, Yang XM, Zhang R (2020) STK3 Suppresses ovarian cancer progression by activating NF-κB signaling to recruit CD8(+) T-cells. J Immunol Res 2020:7263602. https://doi.org/10.1155/2020/7263602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Park J, Kim GH, Lee J, Phuong BTC, Kong B, Won JE, Won GW, Lee YH, Han HD, Lee Y (2020) MST2 silencing induces apoptosis and inhibits tumor growth for estrogen receptor alpha-positive MCF-7 breast cancer. Toxicol Appl Pharmacol 408:115257. https://doi.org/10.1016/j.taap.2020.115257

    Article  CAS  PubMed  Google Scholar 

  31. Jia W, Chen P, Cheng Y (2019) PRDX4 and its roles in various cancers. Technol Cancer Res Treat 18:1533033819864313. https://doi.org/10.1177/1533033819864313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ying B, Xu W, Nie Y, Li Y (2022) HSPA8 is a new biomarker of triple negative breast cancer related to prognosis and immune infiltration. Dis Markers 2022:8446857. https://doi.org/10.1155/2022/8446857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zeng T, Guan Y, Li YK, Wu Q, Tang XJ, Zeng X, Ling H, Zou J (2021) The DNA replication regulator MCM6: an emerging cancer biomarker and target. Clin Chim Acta 517:92–98. https://doi.org/10.1016/j.cca.2021.02.005

    Article  CAS  PubMed  Google Scholar 

  34. Zhao S, Zhang D, Liu S, Huang J (2023) The roles of NOP56 in cancer and SCA36. Pathol Oncol Res. https://doi.org/10.3389/pore.2023.1610884

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2022R1F1A1069631) to YJL and  by Korea Ministry of Environment (MOE) as Graduate School specialized in Climate Change.

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Authors and Affiliations

  1. Department of Integrative Bioscience and Biotechnology, College of Life Science, Sejong University, 209-Neungdong-ro, Gwangjin-gu, 05006, Seoul, Korea

    Rukhsana, Afia Tasnim Supty & YoungJoo Lee

  2. College of Science and Engineering, University of Derby, Kedleston Road, Derby, DE22 1GB, UK

    Rukhsana & Maqbool Hussain

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Contributions

All authors contributed to the study conception and design. Data curation, Methodology, Formal analysis, and Writing—original draft was performed by Rukhsana. Data curation, Writing—review & editing were performed by ATS. Conceptualization, Methodology, Writing—review & editing were performed by MH and Conceptualization, mentoring, Writing—review & editing were performed by YL. All authors read and approved the final manuscript.

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Correspondence to Maqbool Hussain or YoungJoo Lee.

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Rukhsana, Supty, A.T., Hussain, M. et al. STK3 higher expression association with clinical characteristics in intrinsic subtypes of breast cancer invasive ductal carcinoma patients. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07248-3

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