RTKN2, a potential target of breast cancer (BCa), can promote the growth and migration of breast cancer cells

Breast cancer (BCa) is a type of malignancy; however, the exact mechanisms responsible for breast cancer have yet to be elucidated. Rhotekin 2 (RTKN2) is a member of the Rhotekin family. Previous studies demonstrated that RTKN2 is highly expressed in numerous tumors. Previous analysis of the The cancer genome altas (TCGA) database demonstrated that PRKN2 was overexpressed in BCa. However, RTKN2 is rarely reported in BCa and the mechanisms remain unclear. The aim of this study was to elucidate the effect of RTKN2 on the growth of breast cancer cells and investigate the mechanisms involved. Our analysis revealed high expression of RTKN2 in human BCa. The depletion of RTKN2 suppressed the growth of breast cancer cells. In addition, the knockout of RTKN2 restrained the progression of BCa. We also revealed that the knockdown of RTKN2 stimulated cell cycle arrest in BCa. Mechanistically, RTKN2 mediated the Wnt/β-catenin axis to affect the progression of breast cancer. In conclusion, RTKN2 promotes the growth and migration of breast cancer cells by mediating the Wnt/β-catenin axis.

Rhotekin 2 (RTKN2); Breast cancer (BCa); Motility; Cell cycle; Wnt/β-catenin axis

[1] Breast cancer mortality in 500 000 women with early invasive breast cancer in England, 1993–2015: population based observational cohort study. BMJ. 2023; 382: p1744.

[2] Lucarelli AP, Martins MM, Guedes JM. Correlation between the body mass index of patients with breast cancer before and after chemotherapy. European Journal of Gynaecological Oncology. 2017; 38: 187–190.

[3] Huang G, Liang M, Liu H, Huang J, Li P, Wang C, et al. CircRNA hsa_circRNA_104348 promotes hepatocellular carcinoma progression through modulating miR-187-3p/RTKN2 axis and activating Wnt/beta-catenin pathway. Cell Death & Disease. 2020; 11: 1065.

[4] Pang X, Li R, Shi D, Pan X, Ma C, Zhang G, et al. Knockdown of Rhotekin 2 expression suppresses proliferation and induces apoptosis in colon cancer cells. Oncology Letters. 2017; 14: 8028–8034.

[5] Liao J, Dong G, Zhu W, Wulaer B, Mizoguchi H, Sawahata M, et al. Rho kinase inhibitors ameliorate cognitive impairment in a male mouse model of methamphetamine-induced schizophrenia. Pharmacological Research. 2023; 194: 106838.

[6] Ubeysinghe S, Kankanamge D, Thotamune W, Wijayaratna D, Mohan TM, Karunarathne A. Spatiotemporal optical control of Gaq-PLCb interactions. bioRxiv. 2023. [Preprint]

[7] Liao Y, Zeng J, Zhou J, Yang G, Ding K, Zhang X. Silencing of RTKN2 by siRNA suppresses proliferation, and induces G1 arrest and apoptosis in human bladder cancer cells. Molecular Medicine Reports. 2016; 13: 4872–4878.

[8] Wang X, Zhang L, Wang W, Wang Y, Chen Y, Xie R, et al. Rhotekin 2 silencing inhibits proliferation and induces apoptosis in human osteosarcoma cells. Bioscience Reports. 2018; 38: BSR20181384.

[9] Zhao HG, Yin JJ, Chen X, Wu J, Wang W, Tang LW. RTKN2 enhances radioresistance in gastric cancer through regulating the Wnt/b-catenin signalling pathway. Folia Biologica. 2022; 68: 33–39.

[10] Lin Z, Li D, Cheng W, Wu J, Wang K, Hu Y. MicroRNA-181 functions as an antioncogene and mediates NF-kB pathway by targeting RTKN2 in ovarian cancers. Reproductive Sciences. 2019; 26: 1071–1081.

[11] Wei W, Chen H, Liu S. Knockdown of Rhotekin 2 expression suppresses proliferation and invasion and induces apoptosis in hepatocellular carcinoma cells. Molecular Medicine Reports. 2016; 13: 4865–4871.

[12] Derakhshan F, Reis-Filho JS. Pathogenesis of triple-negative breast cancer. Annual Review of Pathology: Mechanisms of Disease. 2022; 17: 181–204.

[13] Jiang YZ, Ma D, Suo C, Shi J, Xue M, Hu X, et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies. Cancer Cell. 2019; 35: 428–440.e425.

[14] Guo Q, Li D, Luo X, Yuan Y, Li T, Liu H, et al. The regulatory network and potential role of LINC00973-miRNA-mRNA ceRNA in the progression of non-small-cell lung cancer. Frontiers in Immunology. 2021; 12: 684807.

[15] Peng B, Ortega J, Gu L, Chang Z, Li GM. Correction: phosphorylation of proliferating cell nuclear antigen promotes cancer progression by activating the ATM/Akt/GSK3b/Snail signaling pathway. Journal of Biological Chemistry. 2020; 295: 9767.

[16] Nusse R, Clevers H. Wnt/b-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017; 169: 985–999.

[17] Nalli M, Masci D, Urbani A, La Regina G, Silvestri R. Emerging direct targeting b-catenin agents. Molecules. 2022; 27: 7735.

[18] Shang S, Hua F, Hu ZW. The regulation of beta-catenin activity and function in cancer: therapeutic opportunities. Oncotarget. 2017; 8: 33972–33989.

[19] Li Y, Jin K, van Pelt GW, van Dam H, Yu X, Mesker WE, et al. c-Myb enhances breast cancer invasion and metastasis through the Wnt/b-Catenin/Axin2 pathway. Cancer Research. 2016; 76: 3364–3375.