ROR2 Promotes Invasion and Chemoresistance of Triple-negative Breast Cancer Cells by Activating PI3K/AKT/mTOR Signaling

Overview

Journal Oncol Res

Specialty Oncology

Date 2024 Jul 1

PMID 38948021

Authors

Xia Da

Han Ge

Junfeng Shi

Chunhua Zhu

Guozhu Wang

Yuan Fang

Jin Xu

Affiliations

Soon will be listed here.

Abstract

Objective: This study aimed to investigate the role of receptor tyrosine kinase-like orphan receptor 2 (ROR2) in triple-negative breast cancer (TNBC).

Methods: ROR2 expression in primary TNBC and metastatic TNBC tissues was analyzed by immunohistochemical staining and PCR. ROR2 expression in TNBC cell lines was detected by PCR and Western blot analysis. The migration, invasion and chemosensitivity of TNBC cells with overexpression or knockdown of ROR2 were examined.

Results: ROR2 expression was high in metastatic TNBC tissues. ROR2 knockdown suppressed the migration, invasion and chemoresistance of TNBC cells. ROR2 overexpression in MDA-MB-435 cells promoted the migration, invasion, and chemoresistance. Moreover, ROR2 knockdown in HC1599 and MDA-MB-435 adriamycin-resistant cells enhanced chemosensitivity to adriamycin. ROR2 could activate PI3K/AKT/mTOR signaling in TNBC cells.

Conclusion: ROR2 is upregulated and promotes metastatic phenotypes of TNBC by activating PI3K/AKT/mTOR signaling.

References

Rehman S, Obaid A, Naz A, Ali A, Kanwal S, Ahmad J . Model-based in silico analysis of the PI3K/Akt pathway: the elucidation of cross-talk between diabetes and breast cancer. PeerJ. 2018; 6:e5917. PMC: 6265603. DOI: 10.7717/peerj.5917. View

Dave H, Butcher D, Anver M, Bollard C . ROR1 and ROR2-novel targets for neuroblastoma. Pediatr Hematol Oncol. 2019; 36(6):352-364. DOI: 10.1080/08880018.2019.1646365. View

Si H, Zhao N, Pedroza A, Zaske A, Rosen J, Creighton C . Noncanonical Wnt/Ror2 signaling regulates cell-matrix adhesion to prompt directional tumor cell invasion in breast cancer. Mol Biol Cell. 2022; 33(11):ar103. PMC: 9582800. DOI: 10.1091/mbc.E22-02-0055. View

Menck K, Heinrichs S, Baden C, Bleckmann A . The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention. Cells. 2021; 10(1). PMC: 7828172. DOI: 10.3390/cells10010142. View

Chen W, Wang G, Zhang G . Insights into the transition of ductal carcinoma to invasive ductal carcinoma: morphology, molecular portraits, and the tumor microenvironment. Cancer Biol Med. 2022; 19(10). PMC: 9630521. DOI: 10.20892/j.issn.2095-3941.2022.0440. View

Ma B, Shao H, Jiang X, Wang Z, Wu C, Whaley D . Akt isoforms differentially provide for chemoresistance in prostate cancer. Cancer Biol Med. 2021; . PMC: 9196054. DOI: 10.20892/j.issn.2095-3941.2020.0747. View

Khan M, Jain V, Rizwanullah M, Ahmad J, Jain K . PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a review on drug discovery and future challenges. Drug Discov Today. 2019; 24(11):2181-2191. DOI: 10.1016/j.drudis.2019.09.001. View

Menck K, Heinrichs S, Wlochowitz D, Sitte M, Noeding H, Janshoff A . WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer. J Exp Clin Cancer Res. 2021; 40(1):395. PMC: 8672621. DOI: 10.1186/s13046-021-02187-z. View

Frenquelli M, Caridi N, Antonini E, Storti F, Vigano V, Gaviraghi M . The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation. Leukemia. 2019; 34(1):257-270. PMC: 7617051. DOI: 10.1038/s41375-019-0486-9. View

10.

Wright T, Brannon A, Gordan J, Mikels A, Mitchell C, Chen S . Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma. Oncogene. 2009; 28(27):2513-23. PMC: 2771692. DOI: 10.1038/onc.2009.116. View

11.

Guo M, Ma G, Zhang X, Tang W, Shi J, Wang Q . ROR2 knockdown suppresses breast cancer growth through PI3K/ATK signaling. Aging (Albany NY). 2020; 12(13):13115-13127. PMC: 7377870. DOI: 10.18632/aging.103400. View

12.

Xu J, Shi J, Tang W, Jiang P, Guo M, Zhang B . ROR2 promotes the epithelial-mesenchymal transition by regulating MAPK/p38 signaling pathway in breast cancer. J Cell Biochem. 2020; 121(10):4142-4153. DOI: 10.1002/jcb.29666. View

13.

Costa R, Han H, Gradishar W . Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. 2018; 169(3):397-406. DOI: 10.1007/s10549-018-4697-y. View

14.

Wang B, Tang Z, Gong H, Zhu L, Liu X . Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. Biosci Rep. 2017; 37(6). PMC: 5705780. DOI: 10.1042/BSR20171092. View

15.

Schroeder M, Rastogi P, Geyer Jr C, Miller L, Thomas A . Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010-2014. Oncologist. 2018; 23(4):481-488. PMC: 5896714. DOI: 10.1634/theoncologist.2017-0398. View

16.

Sporikova Z, Koudelakova V, Trojanec R, Hajduch M . Genetic Markers in Triple-Negative Breast Cancer. Clin Breast Cancer. 2018; 18(5):e841-e850. DOI: 10.1016/j.clbc.2018.07.023. View

17.

Siegel R, Miller K, Jemal A . Cancer statistics, 2020. CA Cancer J Clin. 2020; 70(1):7-30. DOI: 10.3322/caac.21590. View

18.

Balakrishnan S, Mukherjee S, Das S, Bhat F, Raja Singh P, Ranjan Patra C . Gold nanoparticles-conjugated quercetin induces apoptosis via inhibition of EGFR/PI3K/Akt-mediated pathway in breast cancer cell lines (MCF-7 and MDA-MB-231). Cell Biochem Funct. 2017; 35(4):217-231. DOI: 10.1002/cbf.3266. View

19.

Murugan A . mTOR: Role in cancer, metastasis and drug resistance. Semin Cancer Biol. 2019; 59:92-111. DOI: 10.1016/j.semcancer.2019.07.003. View

20.

Navaei Z, Khalili-Tanha G, Zangouei A, Abbaszadegan M, Moghbeli M . PI3K/AKT signaling pathway as a critical regulator of Cisplatin response in tumor cells. Oncol Res. 2023; 29(4):235-250. PMC: 10208004. DOI: 10.32604/or.2022.025323. View