MicroRNA-484 / Akt axis in the regulation of breast cancer cells sensitivity to antitumor drugs

The development of acquired resistance of malignant tumors to specific drugs, such as target and hormonal drugs, is usually associated with a rearrangement of the intracellular signaling network and activation of unblocked growth pathways. Epigenetic regulators, in particular, non-coding miRNAs that control the level of expression of specific signaling proteins, are directly involved in the development and maintenance of such changes. We have previously shown that the development of resistance of breast cancer cells to mTOR (mammalian target of rapamycin) inhibitors and hormonal drugs is accompanied by constitutive activation of protein kinase Akt, the key anti-apoptotic protein.
Aim. To study the role of microRNAs in the regulation of Akt expression and the formation of a resistant phenotype of breast cancer cells.
We have shown that Akt activation in the tamoxifen- or rapamycin-resistant MCF-7 sublines is associated with a decrease in the level of miRNA-484, one of the Akt suppressors. Transfection of microRNA-484 into MCF-7 cells does not affect the activity of estrogen signaling, but leads to a marked decrease in Akt expression and is accompanied by an increase in cell sensitivity to tamoxifen and rapamycin. The obtained data demonstrate the involvement of the miRNA-484 / Akt axis in the breast cancer cells’ sensitization to target and hormonal drugs, which allows us to consider miRNA-484 as a potential candidate for drug development to cure resistant cancers.

1. Shchegolev Y., Sorokin D., Scherbakov A. et al. Upregulation of Akt/Raptor signaling is associated with rapamycin resistance of breast cancer cells. Chem Biol Interact 2020;330:109243. DOI: 10.1016/j.cbi.2020.109243

2. Semina S.E., Scherbakov A.M., Vnukova A.A. et al. Exosomemediated transfer of cancer cell resistance to antiestrogen drugs. Molecules 2018;23(4):829. DOI: 10.3390/molecules23040829

3. Scherbakov A.M., Sorokin D.V., Tatarskiy V.V. Jr. et al. The phenomenon of acquired resistance to metformin in breast cancer cells: the interaction of growth pathways and estrogen receptor signaling. IUBMB Life 2016;68(4):281–92. DOI: 10.1002/iub.1481

4. Liu J., Li S.M. MiR-484 suppressed proliferation, migration, invasion and induced apoptosis of gastric cancer via targeting CCL-18. Int J Exp Pathol 2020;101(6):203–14. DOI: 10.1111/iep.12366

5. Holubekova V., Kolkova Z., Grendar M. et al. Pathway analysis of selected circulating miRNAs in plasma of breast cancer patients: a preliminary study. Int J Mol Sci 2020;21(19):7288. DOI: 10.3390/ijms21197288

6. Wie Y., Li H., Qu Q. MiR-484 suppresses endocrine therapyresistant cells by inhibiting KLF4-induced cancer stem cells in estrogen receptor-positive cancers. Breast Cancer 2021;28(1): 175–86. DOI: 10.1007/s12282-020-01152-6

7. Shi W., Dong F., Jiang Y. et al. Construction of prognostic microRNA signature for human invasive breast cancer by integrated analysis. Onco Targets Ther 2019;12:1979–2010. DOI: 10.2147/OTT.S189265

8. Jia Y.Z., Liu J., Wang G.Q., Song Z.F. MiR-484: a potential biomarker in health and disease. Front Oncol 2022;12:830420. DOI: 10.3389/fonc.2022.830420

9. Semina S.E., Scherbakov A.M., Kovalev S.V. et al. Horizontal transfer of tamoxifen resistance in MCF-7 cell derivates: proteome study. Cancer Invest 2017;35(8):506–18. DOI: 10.1080/07357907.2017.1368081

10. Reid G., Hubner M.R., Metivier R. et al. Cyclic, proteasomemediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. Mol Cell 2003;11:695–707. DOI: 10.1016/S1097-2765(03)00090-X

11. Xu W., Ye C., Qing X. et al. Multi-target tyrosine kinase inhibitor nanoparticle delivery systems for cancer therapy. Mater Today Bio 2022;16:100358. DOI: 10.1016/j.mtbio.2022.100358

12. El Sayed R., El Jamal L., El Iskandarani S. et al. Endocrine and targeted therapy for hormone-receptor-positive, HER2-negative advanced breast cancer: insights to sequencing treatment and overcoming resistance based on clinical trials. Front Oncol 2019;9:510. DOI: 10.3389/fonc.2019.00510

13. Gámez-Chiachio M., Sarrió D., Moreno-Bueno G. Novel therapies and strategies to overcome resistance to anti-HER2-targeted drugs. Cancers (Basel) 2022;14(18):4543. DOI: 10.3390/cancers14184543