Open Access Journal Article

LTBP1 promotes the progression of triple negative breast cancer via activating the RhoA/ROCK signaling pathway

by Jingcheng Zhang a,1 ,  Hong Deng b,1  and  Jun Wang c,*
a
Department of Surgery, Technical University of Munich, Munich, Germany
b
Department of General Surgery, The Affiliated Hospital of Southwest Medical University, Sichuan, China
c
Research Unit Analytical Pathology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
*
Author to whom correspondence should be addressed.
CI  2023, 30; 3(2), 30; https://doi.org/10.58567/ci03020001
Received: 6 December 2023 / Accepted: 22 December 2023 / Published Online: 26 December 2023
View Full-Text
Download PDF

Abstract

The latent transforming growth factor-beta (TGF-β) binding protein 1 (LTBP1) has been implicated in various cellular processes, but its role in triple-negative breast cancer (TNBC) remains unclear. In this study, we investigated the impact of LTBP1 on TNBC progression and its underlying mechanisms. Analysis of online datasets revealed elevated LTBP1 mRNA expression in breast cancer tissues compared to normal adjacent tissues. Kaplan-Meier Plotter analysis indicated that high LTBP1 expression was negatively correlated with relapse-free survival (RFS), distant-metastasis free survival (DMFS), and overall survival (OS) of breast cancer patients. Additionally, LTBP1 mRNA levels were associated with chemotherapy resistance. Functional assays in TNBC cells demonstrated that LTBP1 knockdown suppressed cell proliferation, induced apoptosis, and attenuated migration and invasion. In vivo studies confirmed that LTBP1 knockdown inhibited tumor growth in a xenograft mouse model. Mechanistically, LTBP1 positively correlated with genes involved in signaling regulation and organelle organization, with significant associations to GTPase binding and the RhoA/ROCK pathway. LTBP1 knockdown reduced RhoA activity and phosphorylation of Myosin Light Chain 2 (MLC2), suggesting inhibition of the RhoA/ROCK signaling pathway. Moreover, activation of the RhoA/ROCK pathway partially rescued the effects of LTBP1 knockdown on TNBC cell proliferation, apoptosis, migration, and invasion. In conclusion, our findings suggest that LTBP1 promotes TNBC progression through activation of the RhoA/ROCK signaling pathway, highlighting its potential as a therapeutic target for TNBC.

Keywords: LTBP1; Triple negative breast cancer; RhoA; ROCK; GTPase;
Copyright: © 2023 by Zhang, Deng and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (Creative Commons Attribution 4.0 International License). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Share and Cite

ACS Style
Zhang, J.; Deng, H.; Wang, J. LTBP1 promotes the progression of triple negative breast cancer via activating the RhoA/ROCK signaling pathway. Cancer Insight, 2024, 3, 30. https://doi.org/10.58567/ci03020001
AMA Style
Zhang J, Deng H, Wang J. LTBP1 promotes the progression of triple negative breast cancer via activating the RhoA/ROCK signaling pathway. Cancer Insight; 2024, 3(2):30. https://doi.org/10.58567/ci03020001
Chicago/Turabian Style
Zhang, Jingcheng; Deng, Hong; Wang, Jun 2024. "LTBP1 promotes the progression of triple negative breast cancer via activating the RhoA/ROCK signaling pathway" Cancer Insight 3, no.2:30. https://doi.org/10.58567/ci03020001
APA style
Zhang, J., Deng, H., & Wang, J. (2024). LTBP1 promotes the progression of triple negative breast cancer via activating the RhoA/ROCK signaling pathway. Cancer Insight, 3(2), 30. https://doi.org/10.58567/ci03020001

Article Metrics

Article Access Statistics

References

  1. Qiao Y, Wang B, Yan Y, Niu L. (2022). Long noncoding RNA ST8SIA6-AS1 promotes cell proliferation and metastasis in triple-negative breast cancer by targeting miR-145-5p/CDCA3 to inactivate the p53/p21 signaling pathway. Environ Toxicol 37(10), 2398-2411. https://doi.org/10.1002/tox.23605
  2. Cui S, Zhang Y, Xing L, Li R, Piao Y, Liu H. (2022). Circular RNA dehydrodolichyl diphosphate synthase facilitated triple-negative breast cancer progression via miR-362-3p/DDX5 axis. Environ Toxicol 37(6), 1483-1494. https://doi.org/10.1002/tox.23500
  3. Liu B, Wang Y, He D, Han G, Wang H, Lin Y, Zhang T, Yi C, Li H. (2023). LTBP1 Gene Expression in the Cerebral Cortex and its Neuroprotective Mechanism in Mice with Postischemic Stroke Epilepsy. Curr Pharm Biotechnol 24(2), 317-329. https://doi.org/10.2174/1389201023666220608091511
  4. Nakajima Y, Miyazono K, Nakamura H. (1999). Immunolocalization of latent transforming growth factor-beta binding protein-1 (LTBP1) during mouse development: possible roles in epithelial and mesenchymal cytodifferentiation. Cell Tissue Res 295(2), 257-267. https://doi.org/10.1007/s004410051232
  5. Przyklenk M, Georgieva VS, Metzen F, Mostert S, Kobbe B, Callewaert B, Sengle G, Brachvogel B, Mecham RP, Paulsson M et al. (2022). LTBP1 promotes fibrillin incorporation into the extracellular matrix. Matrix Biol 110, 60-75. https://doi.org/10.1016/j.matbio.2022.04.004
  6. Summers KM, Bush SJ, Davis MR, Hume DA, Keshvari S, West JA. (2023). Fibrillin-1 and asprosin, novel players in metabolic syndrome. Mol Genet Metab 138(1), 106979. https://doi.org/10.1016/j.ymgme.2022.106979
  7. Williamson DB, Sohn CJ, Ito A, Haltiwanger RS. (2021). POGLUT2 and POGLUT3 O-glucosylate multiple EGF repeats in fibrillin-1, -2, and LTBP1 and promote secretion of fibrillin-1. The Journal of biological chemistry 297(3), 101055. https://doi.org/10.1016/j.jbc.2021.101055
  8. Zhao Q, Zheng K, Ma C, Li J, Zhuo L, Huang W, Chen T, Jiang Y. (2020). PTPS Facilitates Compartmentalized LTBP1 S-Nitrosylation and Promotes Tumor Growth under Hypoxia. Molecular cell 77(1), 95-107.e105. https://doi.org/10.1016/j.molcel.2019.09.018
  9. Bartha Á, Győrffy B. (2021). TNMplot.com: A Web Tool for the Comparison of Gene Expression in Normal, Tumor and Metastatic Tissues. International journal of molecular sciences 22(5). https://doi.org/10.3390/ijms22052622
  10. Győrffy B. (2023). Discovery and ranking of the most robust prognostic biomarkers in serous ovarian cancer. GeroScience 45(3), 1889-1898. https://doi.org/10.1007/s11357-023-00742-4
  11. Fekete JT, Győrffy B. (2019). ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti-HER2 therapy using transcriptomic data of 3,104 breast cancer patients. Int J Cancer 145(11), 3140-3151. https://doi.org/10.1002/ijc.32369
  12. Yin L, Duan JJ, Bian XW, Yu SC. (2020). Triple-negative breast cancer molecular subtyping and treatment progress. Breast cancer research BCR 22(1), 61. https://doi.org/10.1186/s13058-020-01296-5
  13. Liu Y, Chen Y, Zhao Q, Xie T, Xiang C, Guo Q, Zhang W, Zhou Y, Yuan Y, Zhang Y et al. (2023). A positive TGF-β/miR-9 regulatory loop promotes the expansion and activity of tumour-initiating cells in breast cancer. British journal of pharmacology 180(17), 2280-2297. https://doi.org/10.1111/bph.16092
  14. Cai R, Wang P, Zhao X, Lu X, Deng R, Wang X, Su Z, Hong C, Lin J. (2020). LTBP1 promotes esophageal squamous cell carcinoma progression through epithelial-mesenchymal transition and cancer-associated fibroblasts transformation. J Transl Med 18(1), 139. https://doi.org/10.1186/s12967-020-02310-2
  15. Hu J, Li X, Guo X, Guo Q, Xiang C, Zhang Z, Xing Y, Xi T, Zheng L. (2017). The CCR2 3'UTR functions as a competing endogenous RNA to inhibit breast cancer metastasis. Journal of cell science 130(19), 3399-3413. https://doi.org/10.1242/jcs.202127
  16. Li X, Zheng L, Zhang F, Hu J, Chou J, Liu Y, Xing Y, Xi T. (2016). STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer. Oncotarget 7(17), 23197-23211. https://doi.org/10.18632/oncotarget.8099
  17. Wang J, Zhong Q, Zhang H, Liu S, Li S, Xia T, Xiao Z, Chen R, Ye Y, Liang F et al. (2022). Nogo-B promotes invasion and metastasis of nasopharyngeal carcinoma via RhoA-SRF-MRTFA pathway. Cell death & disease 13(1), 76. https://doi.org/10.1038/s41419-022-04518-0
  18. Juríková M, Danihel Ľ, Polák Š, Varga I. (2016). Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. Acta histochemica 118(5), 544-552. https://doi.org/10.1016/j.acthis.2016.05.002
  19. Fürst R. (2016). Narciclasine - an Amaryllidaceae Alkaloid with Potent Antitumor and Anti-Inflammatory Properties. Planta Med 82(16), 1389-1394. https://doi.org/10.1055/s-0042-115034
  20. Van Goietsenoven G, Mathieu V, Lefranc F, Kornienko A, Evidente A, Kiss R. (2013). Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers. Med Res Rev 33(2), 439-455. https://doi.org/10.1002/med.21253
  21. Tang R, Jia L, Li Y, Zheng J, Qi P. (2021). Narciclasine attenuates sepsis-induced myocardial injury by modulating autophagy. Aging (Albany NY) 13(11), 15151-15163. https://doi.org/10.18632/aging.203078
  22. Lin R, Li X, Wu S, Qian S, Hou H, Dong M, Zhang X, Zhang M. (2021). Suppression of latent transforming growth factor-β (TGF-β)-binding protein 1 (LTBP1) inhibits natural killer/ T cell lymphoma progression by inactivating the TGF-β/Smad and p38(MAPK) pathways. Experimental cell research 407(1), 112790. https://doi.org/10.1016/j.yexcr.2021.112790