Cover Image

Expression Analysis of miRNAs Targeting PIK3CA and AKT1 Genes of PI3K Signaling Pathway in Breast Cancer Cells.

Javad Razaviyan, Razie Hadavi, Samira Mohammadi-Yeganeh
Background: MicroRNAs (miRNAs) are key gene regulators that are involved in many bi­ological and also pathological processes, including breast cancer. Breast cancer is the most common form of malignancies in women and requires new therapies and biomarkers. Different signaling pathways, such as Phosphoinositide 3-kinase (PI3K) signaling pathway are involved in breast cancer and can be new candidates for targeted therapies based on miRNAs. The aim of this study was to predict miRNAs targeting Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and serine/threonine kinase 1 (AKT1) genes of PI3K cascade bioinformatically and to analyze their expression in breast cancer. Materials and Methods: Bioinformatic software and tools were used to predict miRNAs targeting PIK3CA and AKT1 genes. MCF-7 and MCF-10A cell lines were cultured as breast cancer and control cells respec­tively. RNA extraction, cDNA synthesis, and quantitative real-time PCR were performed. REST 2009® was utilized to analyze the expression of miRNAs and their target genes. Results: The results of our bioinformatic predictions indicated that miR-576-5p, miR-501-3p, and miR-3143 can be the first candidate miRNAs targeting PI3K signaling pathway. Data analyses demon­strated that PIK3CA and AKT1 genes were up-regulated while all bioinformatically predicted miRNAs were down-regulated in MCF-7 cell line compared to the normal cells. Conclusion: The results of our study demonstrated that PIK3CA and AKT1 can be targeted by miR-576-5p and miR-501-3p respectively. Furthermore, miR-3143 can target both mRNAs. Since these miRNAs target oncogenes, they can be proposed for new complementary targeted therapies in breast cancer patients. [GMJ.2017;6(4):338-45] DOI: 10.22086/gmj.v6i4.925
Breast cancer; PIK3CA; AKT1; miR-567-5p; miR-501-3p; miR-3143

Huo D, Clayton WM, Yoshimatsu TF, Chen J, Olopade OI. Identification of a circulating MicroRNA signature to distinguish recurrence in breast cancer patients. Oncotarget. 2016;7(34):55231.

Fan D, Ren B, Yang X, Liu J, Zhang Z. Upregulation of miR-501-5p activates the wnt/β-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer. J Exp Clin Cancer Res. 2016;35(1):177.

Venkatesan N, Deepa PR, Khetan V, Krishnakumar S. Computational and in vitro investigation of miRNA-gene regulations in retinoblastoma pathogenesis: miRNA mimics strategy. Bioinform Biol Insights. 2015;9:89.

Wang Q, Li C, Zhu Z, Teng Y, Che X, Wang Y, et al. miR-155-5p antagonizes the apoptotic effect of bufalin in triple-negative breast cancer cells. Anticancer Drugs. 2016;27(1):9-16.

Das SG, Romagnoli M, Mineva ND, Barillé-Nion S, Jézéquel P, Campone M, et al. miR-720 is a downstream target of an ADAM8-induced ERK signaling cascade that promotes the migratory and invasive phenotype of triple-negative breast cancer cells. Breast Cancer Res. 2016;18(1):40.

Zhang K, Zhang Y, Liu C, Xiong Y, Zhang J. MicroRNAs in the diagnosis and prognosis of breast cancer and their therapeutic potential (review). Int J Oncol. 2014;45:950-8.

DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin. 2016;66(1):31-42.

Casey MC, Sweeney KJ, Brown JAL, Kerin MJ. Exploring circulating micro‐RNA in the neoadjuvant treatment of breast cancer. International journal of cancer. 2016.

Singh R, Mo YY. Role of microRNAs in breast cancer. Cancer Biol Ther. 2013;14:201-12.

Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V, et al. Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids. 2014;3:e194.

Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Kerin MJ. MicroRNAs as Novel Biomarkers for Breast Cancer. J Oncol. 2009;2009:950201.

Paplomata E, O'Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014;6:154-66.

Huemer F, Bartsch R, Gnant M. The PI3K/AKT/MTOR Signaling Pathway: The Role of PI3K and AKT Inhibitors in Breast Cancer. Curr Breast Cancer Rep. 2014;6:59-70.

Cidado J, Park BH. Targeting the PI3K/Akt/mTOR pathway for breast cancer therapy. J Mammary Gland Biol Neoplasia. 2012;17:205-16.

Adams JR, Schachter NF, Liu JC, Zacksenhaus E, Egan SE. Elevated PI3K signaling drives multiple breast cancer subtypes. Oncotarget. 2011;2:435-47.

Markman B, Dienstmann R, Tabernero J. Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs. Oncotarget. 2010;1:530-43.

Mo W, Liu Q, Lin CC-J, Dai H, Peng Y, Liang Y, et al. mTOR inhibitors suppress homologous recombination repair and synergize with PARP inhibitors via regulating SUV39H1 in BRCA-proficient triple-negative breast cancer. Clin Cancer Res. 2016;22(7):1699-712.

Mohammadi-Yeganeh S, Paryan M, Samiee SM, Soleimani M, Arefian E, Azadmanesh K, et al. Development of a robust, low cost stem-loop real-time quantification PCR technique for miRNA expression analysis. Mol Biol Rep. 2013;40(5):3665-74.

Davis NM, Sokolosky M, Stadelman K, Abrams SL, Libra M, Candido S, et al. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention. Oncotarget. 2014;5:4603-50.

Mukohara T. PI3K mutations in breast cancer: prognostic and therapeutic implications. Breast Cancer (Dove Med Press). 2015;7:111-23.

Chia S, Gandhi S, Joy A, Edwards S, Gorr M, Hopkins S, et al. Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer. Curr Oncol. 2015;22(1):33.

Bhat-Nakshatri P, Goswami CP, Badve S, Magnani L, Lupien M, Nakshatri H. Molecular insights of pathways resulting from two common PIK3CA mutations in breast cancer. Cancer Res. 2016;76(13):3989-4001.

Fleisher B, Clarke C, Ait-Oudhia S. Current advances in biomarkers for targeted therapy in triple-negative breast cancer. Breast Cancer (Dove Med Press). 2016;8:183-97.

Aleskandarany MA, Rakha EA, Ahmed MA, Powe DG, Paish EC, Macmillan RD, et al. PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis. Breast Cancer Res Treat. 2010;122(1):45-53.

Riggio M, Perrone MC, Polo ML, Rodriguez MJ, May M, Abba M, et al. AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins. Sci Rep. 2017; 7: 44244.

Li J, Su W, Zhang S, Hu Y, Liu J, Zhang X, et al. Epidermal growth factor receptor and AKT1 gene copy numbers by multi‐gene fluorescence in situ hybridization impact on prognosis in breast cancer. Cancer Sci. 2015;106(5):642-9.

Heger Z, Gumulec J, Cernei N, Tmejova K, Kopel P, Balvan J, et al. 17β-estradiol-containing liposomes as a novel delivery system for the antisense therapy of ER-positive breast cancer: An in vitro study on the MCF-7 cell line. Oncol Rep. 2015;33(2):921-9.

Li Z, Gu X, Fang Y, Xiang J, Chen Z. microRNA expression profiles in human colorectal cancers with brain metastases. Oncol Lett. 2012;3(2):346-50.

Martínez-Ramos R, García-Lozano J, Lucena J, Castillo-Palma M, García-Hernández F, Rodríguez M, et al. Differential expression pattern of microRNAs in CD4+ and CD19+ cells from asymptomatic patients with systemic lupus erythematosus. Lupus. 2014;23(4):353-9.

Díaz-Prado S, Cicione C, Muiños-López E, Hermida-Gómez T, Oreiro N, Fernández-López C et, al. Characterization of microRNA expression profiles in normal and osteoarthritic human chondrocytes. BMC Musculoskelet Disord. 2012;13(1):144.

Gan X, Liu Z, Tong B, Zhou J. Epigenetic downregulated ITGBL1 promotes non-small cell lung cancer cell invasion through Wnt/PCP signaling. Tumor Biol. 2016;37(2):1663-9.

Ge Y, Zhao K, Qi Y, Min X, Shi Z, Qi X, et al. Serum microRNA expression profile as a biomarker for the diagnosis of pertussis. Mol Biol Rep. 2013;40(2):1325-32.

Larsen AC. Conjunctival malignant melanoma in Denmark: epidemiology, treatment and prognosis with special emphasis on tumorigenesis and genetic profile. Acta Ophthalmol. 2016;94(A103):1-27.

Yılmaz ŞG, Geyik S, Neyal AM, Soko ND, Bozkurt H, Dandara C. Hypothesis: Do miRNAs Targeting the Leucine-Rich Repeat Kinase 2 Gene (LRRK2) Influence Parkinson's Disease Susceptibility? OMICS. 2016;20(4):224-8.


  • There are currently no refbacks.