MiR-146a-5p Promotes Angiogenesis and Confers Trastuzumab Resistance in HER2+ Breast Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2023 Apr 13

PMID 37046799

Authors

Paula Cabello

Sandra Torres-Ruiz

Anna Adam-Artigues

Jaume Fores-Martos

Maria Teresa Martinez

Cristina Hernando

Sandra Zazo

Juan Madoz-Gurpide

Ana Rovira

Octavio Burgues

Federico Rojo

Joan Albanell

Ana Lluch

Begona Bermejo

Juan Miguel Cejalvo

Pilar Eroles

Affiliations

Soon will be listed here.

Abstract

Trastuzumab treatment has significantly improved the prognosis of HER2-positive breast cancer patients. Despite this, resistance to therapy still remains the main clinical challenge. In order to evaluate the implication of microRNAs in the trastuzumab response, we performed a microRNA array in parental and acquired trastuzumab-resistant HER2-positive breast cancer cell lines. Our results identified miR-146a-5p as the main dysregulated microRNA. Interestingly, high miR-146a-5p expression in primary tumor tissue significantly correlated with shorter disease-free survival in HER2-positive breast cancer patients. The gain- and loss-of-function of miR-146a-5p modulated the response to trastuzumab. Furthermore, the overexpression of miR-146a-5p increased migration and angiogenesis, and promoted cell cycle progression by reducing CDKN1A expression. Exosomes from trastuzumab-resistant cells showed a high level of miR-146a-5p expression compared with the parental cells. In addition, the co-culture with resistant cells' exosomes was able to decrease in sensitivity and increase the migration capacities in trastuzumab-sensitive cells, as well as angiogenesis in HUVEC-2 cells. Collectively, these data support the role of miR-146a-5p in resistance to trastuzumab, and demonstrate that it can be transferred by exosomes conferring resistance properties to other cells.

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References

Hong L, Han Y, Lu Q, Zhang H, Zhao Q, Wu K . Drug resistance-related microRNAs in esophageal cancer. Expert Opin Biol Ther. 2012; 12(11):1487-94. DOI: 10.1517/14712598.2012.711309. View

Milano G, Biemmi V, Lazzarini E, Balbi C, Ciullo A, Bolis S . Intravenous administration of cardiac progenitor cell-derived exosomes protects against doxorubicin/trastuzumab-induced cardiac toxicity. Cardiovasc Res. 2019; 116(2):383-392. DOI: 10.1093/cvr/cvz108. View

Samuel P, Fabbri M, Carter D . Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles. Proteomics. 2017; 17(23-24). DOI: 10.1002/pmic.201600375. View

Yuwen D, Sheng B, Liu J, Wenyu W, Shu Y . MiR-146a-5p level in serum exosomes predicts therapeutic effect of cisplatin in non-small cell lung cancer. Eur Rev Med Pharmacol Sci. 2017; 21(11):2650-2658. View

Zhang H, Jiang L, Hou J, Zhong S, Zhu L, Wang D . Exosome: a novel mediator in drug resistance of cancer cells. Epigenomics. 2018; 10(11):1499-1509. DOI: 10.2217/epi-2017-0151. View

Kim V, Nam J . Genomics of microRNA. Trends Genet. 2006; 22(3):165-73. DOI: 10.1016/j.tig.2006.01.003. View

Tormo E, Adam-Artigues A, Ballester S, Pineda B, Zazo S, Gonzalez-Alonso P . The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene. Sci Rep. 2017; 7:41309. PMC: 5264595. DOI: 10.1038/srep41309. View

Han M, Hu J, Lu P, Cao H, Yu C, Li X . Exosome-transmitted miR-567 reverses trastuzumab resistance by inhibiting ATG5 in breast cancer. Cell Death Dis. 2020; 11(1):43. PMC: 6976584. DOI: 10.1038/s41419-020-2250-5. View

Zhu H, Bai W, Liu J, Zheng Z, Guan H, Zhou Q . Up-regulation of FGFBP1 signaling contributes to miR-146a-induced angiogenesis in human umbilical vein endothelial cells. Sci Rep. 2016; 6:25272. PMC: 4848533. DOI: 10.1038/srep25272. View

10.

Yang S, Ma S, Dou H, Liu F, Zhang S, Jiang C . Breast cancer-derived exosomes regulate cell invasion and metastasis in breast cancer via miR-146a to activate cancer associated fibroblasts in tumor microenvironment. Exp Cell Res. 2020; 391(2):111983. DOI: 10.1016/j.yexcr.2020.111983. View

11.

Iorio M, Ferracin M, Liu C, Veronese A, Spizzo R, Sabbioni S . MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005; 65(16):7065-70. DOI: 10.1158/0008-5472.CAN-05-1783. View

12.

Bobrie A, Krumeich S, Reyal F, Recchi C, Moita L, Seabra M . Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 2012; 72(19):4920-30. DOI: 10.1158/0008-5472.CAN-12-0925. View

13.

Perez-Hernandez J, Olivares D, Forner M, Ortega A, Solaz E, Martinez F . Urinary exosome miR-146a is a potential marker of albuminuria in essential hypertension. J Transl Med. 2018; 16(1):228. PMC: 6092786. DOI: 10.1186/s12967-018-1604-6. View

14.

Gagliato D, Fontes Jardim D, Marchesi M, Hortobagyi G . Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget. 2016; 7(39):64431-64446. PMC: 5325455. DOI: 10.18632/oncotarget.7043. View

15.

Chakrabarty A, Rexer B, Wang S, Cook R, Engelman J, Arteaga C . H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene. 2010; 29(37):5193-203. PMC: 2945381. DOI: 10.1038/onc.2010.257. View

16.

Kim H, Lee S, Shin E, Seong K, Jin Y, Youn H . The Emerging Roles of Exosomes as EMT Regulators in Cancer. Cells. 2020; 9(4). PMC: 7226841. DOI: 10.3390/cells9040861. View

17.

Chen W, Cai Y, Lv M, Chen L, Zhong S, Ma T . Exosomes from docetaxel-resistant breast cancer cells alter chemosensitivity by delivering microRNAs. Tumour Biol. 2014; 35(10):9649-59. DOI: 10.1007/s13277-014-2242-0. View

18.

Yu D, Wu Y, Shen H, Lv M, Chen W, Zhang X . Exosomes in development, metastasis and drug resistance of breast cancer. Cancer Sci. 2015; 106(8):959-64. PMC: 4556383. DOI: 10.1111/cas.12715. View

19.

Harper J, Elledge S, Keyomarsi K, Dynlacht B, Tsai L, Zhang P . Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell. 1995; 6(4):387-400. PMC: 301199. DOI: 10.1091/mbc.6.4.387. View

20.

Warnecke-Eberz U, Chon S, Holscher A, Drebber U, Bollschweiler E . Exosomal onco-miRs from serum of patients with adenocarcinoma of the esophagus: comparison of miRNA profiles of exosomes and matching tumor. Tumour Biol. 2015; 36(6):4643-53. DOI: 10.1007/s13277-015-3112-0. View