Expanding the Biotherapeutics Realm via miR-34a: “Potent Clever Little” Agent in Breast Cancer Therapy

Author(s): Mohsen Mohammady, Seyed I. Ghetmiri, Mahtab Baharizade, Mohammad H. Morowvat*, Susan Torabi

Journal Name: Current Pharmaceutical Biotechnology

Volume 20 , Issue 8 , 2019

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Graphical Abstract:


Background: One of the most prevalent cancers befell to women is considered to be breast cancer (BC). It is also the deadliest among the female population after lung cancer. Additionally, several studies have demonstrated that there is an association between microRNA34-a and breast cancer.

Methods: We searched PubMed, Web of Science, and Google Scholar up to December 2018. Those studies which have been studied miR-34a and its tumor-suppressing capabilities were considered as the most important topics. Moreover, we extracted articles which were solely focused on microRNA-34a in breast cancer therapy. Finally, 80 articles were included.

Results: In comparison with the normal tissues, down-regulation of miR-34a expression is shown considerably in tumor cells. Overexpression of miR-34a acts as a tumor suppressor by transcriptional regulating one of the signaling pathways (TP53), NOTCH, and transforming growth factor beta (TGF-β), Bcl- 2 and SIRT1genes, HDAC1 and HDAC7, Fra-1, TPD52, TLR Via CXCL10. Moreover, drug resistance declines which lead to the apoptosis, cell cycle arrest and senescence. As a result, the proliferation, invasion and metastasis of the tumor are suppressed. The Mrx34 drug contains miR-34a mimic and a lipid vector. MiR-34a as the active ingredient portrays the role of a tumor suppressor. This drug has recently entered the clinical trials studies.

Conclusion: These findings suggest a robust cause for developing miR-34a as a therapeutic agent to target BC. In that scenario, miR-34a is strongly useful to introduce new therapeutic goals for BC. Moreover, this review aims to confirm the signal pathways, therapeutic and diagnostic values of miR- 34a in BC and beyond.

Keywords: Biopharmaceuticals, breast cancer, microRNAs, miR-34a, nucleic acid-based therapeutics, pharmaceutical biotechnology, tumor suppressor.

Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J.; Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA, 2003, 100(7), 3983-3988.
DeSantis, C.E.; Fedewa, S.A.; Goding Sauer, A.; Kramer, J.L.; Smith, R.A.; Jemal, A. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J. Clin., 2016, 66(1), 31-42.
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin., 2017, 67(1), 7-30.
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
Gangopadhyay, S.; Nandy, A.; Hor, P.; Mukhopadhyay, A. Breast cancer stem cells: A novel therapeutic target. Clin. Breast Cancer, 2013, 13(1), 7-15.
Zhang, Z.; Wang, J.; Skinner, K.A.; Shayne, M.; Hajdu, S.I.; Bu, H.; Hicks, D.G.; Tang, P. Pathological features and clinical outcomes of breast cancer according to levels of oestrogen receptor expression. Histopathology, 2014, 65(4), 508-516.
Calin, G.A.; Dumitru, C.D.; Shimizu, M.; Bichi, R.; Zupo, S.; Noch, E.; Aldler, H.; Rattan, S.; Keating, M.; Rai, K.; Rassenti, L.; Kipps, T.; Negrini, M.; Bullrich, F.; Croce, C.M. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA, 2002, 99(24), 15524-15529.
Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 2004, 116(2), 281-297.
Bartel, D.P. MicroRNAs: Target recognition and regulatory functions. Cell, 2009, 136(2), 215-233.
Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 2005, 120(1), 15-20.
Chen, C-Z.; Li, L.; Lodish, H.F.; Bartel, D.P. MicroRNAs modulate hematopoietic lineage differentiation. Science, 2004, 303(5654), 83-86.
Rovira, C.; Güida, M.C.; Cayota, A. MicroRNAs and other small silencing RNAs in cancer. IUBMB Life, 2010, 62(12), 859-868.
Friedman, R.C.; Farh, K.K-H.; Burge, C.B.; Bartel, D.P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res., 2009, 19(1), 92-105.
Chang, C-J.; Chao, C-H.; Xia, W.; Yang, J-Y.; Xiong, Y.; Li, C-W.; Yu, W-H.; Rehman, S.K.; Hsu, J.L.; Lee, H-H.; Liu, M.; Chen, C.T.; Yu, D.; Hung, M.C. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol., 2011, 13(3), 317-323.
Tivnan, A.; Tracey, L.; Buckley, P.G.; Alcock, L.C.; Davidoff, A.M.; Stallings, R.L. MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma. BMC Cancer, 2011, 11(1), 33.
Roy, S.; Levi, E.; Majumdar, A.P.; Sarkar, F.H. Expression of miR-34 is lost in colon cancer which can be re-expressed by a novel agent CDF. J. Hematol. Oncol., 2012, 5(1), 58.
Wu, M-Y.; Fu, J.; Xiao, X.; Wu, J.; Wu, R-C. MiR-34a regulates therapy resistance by targeting HDAC1 and HDAC7 in breast cancer. Cancer Lett., 2014, 354(2), 311-319.
Gallardo, E.; Navarro, A.; Viñolas, N.; Marrades, R.M.; Diaz, T.; Gel, B.; Quera, A.; Bandres, E.; Garcia-Foncillas, J.; Ramirez, J.; Monzo, M. miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer. Carcinogenesis, 2009, 30(11), 1903-1909.
Steeg, P.S. Tumor metastasis: Mechanistic insights and clinical challenges. Nat. Med., 2006, 12(8), 895-904.
Chaffer, C.L.; Weinberg, R.A. A perspective on cancer cell metastasis. Science, 2011, 331(6024), 1559-1564.
Rivera, E.; Gomez, H. Chemotherapy resistance in metastatic breast cancer: The evolving role of ixabepilone. Breast Cancer Res., 2010, 12(2)(Suppl. 2), S2.
Naumov, G.N.; Townson, J.L.; MacDonald, I.C.; Wilson, S.M.; Bramwell, V.H.; Groom, A.C.; Chambers, A.F. Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res. Treat., 2003, 82(3), 199-206.
Wang, J.; Zhang, X.; Wang, L.; Yang, Y.; Dong, Z.; Wang, H.; Du, L.; Wang, C. MicroRNA-214 suppresses oncogenesis and exerts impact on prognosis by targeting PDRG1 in bladder cancer. PLoS One, 2015, 10(2)e0118086
Calin, G.A.; Croce, C.M. MicroRNA-cancer connection: The beginning of a new tale. Cancer Res., 2006, 66(15), 7390-7394.
van Kouwenhove, M.; Kedde, M.; Agami, R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat. Rev. Cancer, 2011, 11(9), 644-656.
Bian, H-B.; Pan, X.; Yang, J-S.; Wang, Z-X.; De, W. Upregulation of microRNA-451 increases cisplatin sensitivity of non-small cell lung cancer cell line (A549). J. Exp. Clin. Cancer Res., 2011, 30(1), 20.
Zhang, B.; Pan, X.; Cobb, G.P.; Anderson, T.A. microRNAs as oncogenes and tumor suppressors. Dev. Biol., 2007, 302(1), 1-12.
Le Quesne, J.; Caldas, C. Micro-RNAs and breast cancer. Mol. Oncol., 2010, 4(3), 230-241.
Gerlinger, M.; Rowan, A.J.; Horswell, S.; Math, M.; Larkin, J.; Endesfelder, D.; Gronroos, E.; Martinez, P.; Matthews, N.; Stewart, A.; Tarpey, P.; Varela, I.; Phillimore, B.; Begum, S.; McDonald, N.Q.; Butler, A.; Jones, D.; Raine, K.; Latimer, C.; Santos, C.R.; Nohadani, M.; Eklund, A.C.; Spencer-Dene, B.; Clark, G.; Pickering, L.; Stamp, G.; Gore, M.; Szallasi, Z.; Downward, J.; Futreal, P.A.; Swanton, C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med., 2012, 366(10), 883-892.
Misso, G.; Di Martino, M.T.; De Rosa, G.; Farooqi, A.A.; Lombardi, A.; Campani, V.; Zarone, M.R.; Gullà, A.; Tagliaferri, P.; Tassone, P.; Caraglia, M. Mir-34: A new weapon against cancer? Mol. Ther. Nucleic Acids, 2014, 3e, 194.
Mlcochova, H.; Machackova, T.; Rabien, A.; Radova, L.; Fabian, P.; Iliev, R.; Slaba, K.; Poprach, A.; Kilic, E.; Stanik, M. Epithelial-mesenchymal transition-associated microRNA/mRNA signature is linked to metastasis and prognosis in clear-cell renal cell carcinoma. Sci. Rep., 2016, 6, 31852.
Hermeking, H. The miR-34 family in cancer and apoptosis. Cell Death Differ., 2010, 17(2), 193-199.
Imani, S.; Hosseinifard, H.; Cheng, J.; Wei, C.; Fu, J. Prognostic value of EMT-inducing transcription factors (EMT-TFs) in metastatic breast cancer: A systematic review and meta-analysis. Sci. Rep., 2016, 6, 28587.
Pang, R.T.; Leung, C.O.; Ye, T-M.; Liu, W.; Chiu, P.C.; Lam, K.K.; Lee, K-F.; Yeung, W.S. MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells. Carcinogenesis, 2010, 31(6), 1037-1044.
Pang, M.F.; Georgoudaki, A.M.; Lambut, L.; Johansson, J.; Tabor, V.; Hagikura, K.; Jin, Y.; Jansson, M.; Alexander, J.S.; Nelson, C.M.; Jakobsson, L.; Betsholtz, C.; Sund, M.; Karlsson, M.C.; Fuxe, J. TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis. Oncogene, 2016, 35(6), 748-760.
Ginestier, C.; Liu, S.; Diebel, M.E.; Korkaya, H.; Luo, M.; Brown, M.; Wicinski, J.; Cabaud, O.; Charafe-Jauffret, E.; Birnbaum, D.; Guan, J.L.; Dontu, G.; Wicha, M.S. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J. Clin. Invest., 2010, 120(2), 485-497.
Kang, L.; Mao, J.; Tao, Y.; Song, B.; Ma, W.; Lu, Y.; Zhao, L.; Li, J.; Yang, B.; Li, L. MicroRNA-34a suppresses the breast cancer stem cell-like characteristics by downregulating Notch1 pathway. Cancer Sci., 2015, 106(6), 700-708.
Zhang, H.; Li, N.; Zhang, J.; Jin, F.; Shan, M.; Qin, J.; Wang, Y. The influence of miR-34a expression on stemness and cytotoxic susceptibility of breast cancer stem cells. Cancer Biol. Ther., 2016, 17(6), 614-624.
Liu, T.; Liu, P.Y.; Marshall, G.M. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res., 2009, 69(5), 1702-1705.
Luo, J.; Nikolaev, A.Y.; Imai, S.; Chen, D.; Su, F.; Shiloh, A.; Guarente, L.; Gu, W. Negative control of p53 by Sir2α promotes cell survival under stress. Cell, 2001, 107(2), 137-148.
Lee, J.T.; Gu, W. SIRT1: Regulator of p53 deacetylation. Genes Cancer, 2013, 4(3-4), 112-117.
Yamakuchi, M.; Ferlito, M.; Lowenstein, C.J. miR-34a repression of SIRT1 regulates apoptosis. Proc. Natl. Acad. Sci. USA, 2008, 105(36), 13421-13426.
Yamakuchi, M.; Lowenstein, C.J. MiR-34, SIRT1 and p53: the feedback loop. Cell Cycle, 2009, 8(5), 712-715.
Ma, W.; Xiao, G.G.; Mao, J.; Lu, Y.; Song, B.; Wang, L.; Fan, S.; Fan, P.; Hou, Z.; Li, J.; Yu, X.; Wang, B.; Wang, H.; Wang, H.; Xu, F.; Li, Y.; Liu, Q.; Li, L. Dysregulation of the miR-34a-SIRT1 axis inhibits breast cancer stemness. Oncotarget, 2015, 6(12), 10432-10444.
Li, L.; Yuan, L.; Luo, J.; Gao, J.; Guo, J.; Xie, X. MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clin. Exp. Med., 2013, 13(2), 109-117.
Li, L.; Xie, X.; Luo, J.; Liu, M.; Xi, S.; Guo, J.; Kong, Y.; Wu, M.; Gao, J.; Xie, Z.; Tang, J.; Wang, X.; Wei, W.; Yang, M.; Hung, M.C.; Xie, X. Targeted expression of miR-34a using the T-VISA system suppresses breast cancer cell growth and invasion. Mol. Ther., 2012, 20(12), 2326-2334.
Zhao, G.; Guo, J.; Li, D.; Jia, C.; Yin, W.; Sun, R.; Lv, Z.; Cong, X. MicroRNA-34a suppresses cell proliferation by targeting LMTK3 in human breast cancer mcf-7 cell line. DNA Cell Biol., 2013, 32(12), 699-707.
Li, X.J.; Ji, M.H.; Zhong, S.L.; Zha, Q.B.; Xu, J.J.; Zhao, J.H.; Tang, J.H. MicroRNA-34a modulates chemosensitivity of breast cancer cells to adriamycin by targeting Notch1. Arch. Med. Res., 2012, 43(7), 514-521.
Yang, S.; Li, Y.; Gao, J.; Zhang, T.; Li, S.; Luo, A.; Chen, H.; Ding, F.; Wang, X.; Liu, Z. MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene, 2013, 32(36), 4294-4303.
Mitra, A.K.; Agrahari, V.; Mandal, A.; Cholkar, K.; Natarajan, C.; Shah, S.; Joseph, M.; Trinh, H.M.; Vaishya, R.; Yang, X. Novel delivery approaches for cancer therapeutics. J. Control. Release, 2015, 219, 248-268.
Meacham, C.E.; Morrison, S.J. Tumour heterogeneity and cancer cell plasticity. Nature, 2013, 501(7467), 328-337.
Magee, J.A.; Piskounova, E.; Morrison, S.J. Cancer stem cells: Impact, heterogeneity, and uncertainty. Cancer Cell, 2012, 21(3), 283-296.
He, Q.; Guo, S.; Qian, Z.; Chen, X. Development of individualized anti-metastasis strategies by engineering nanomedicines. Chem. Soc. Rev., 2015, 44(17), 6258-6286.
Cullis, P.R.; Hope, M.J. Lipid nanoparticle systems for enabling gene therapies. Mol. Ther., 2017, 25(7), 1467-1475.
Xu, M.; Li, D.; Yang, C.; Ji, J-S. MicroRNA-34a inhibition of the TLR signaling pathway via CXCL10 suppresses breast cancer cell invasion and migration. Cell. Physiol. Biochem., 2018, 46(3), 1286-1304.
Haussecker, D. The business of RNAi therapeutics in 2012. Mol. Ther. Nucleic Acids, 2012, 1e8
Walsh, G. Biopharmaceutical benchmarks 2018. Nat. Biotechnol., 2018, 36(12), 1136-1145.
Tolcher, A.W.; Rodrigueza, W.V.; Rasco, D.W.; Patnaik, A.; Papadopoulos, K.P.; Amaya, A.; Moore, T.D.; Gaylor, S.K.; Bisgaier, C.L.; Sooch, M.P.; Woolliscroft, M.J.; Messmann, R.A. A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors. Cancer Chemother. Pharmacol., 2014, 73(2), 363-371.
Beg, M.S.; Brenner, A.J.; Sachdev, J.; Borad, M.; Kang, Y-K.; Stoudemire, J.; Smith, S.; Bader, A.G.; Kim, S.; Hong, D.S. Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Invest. New Drugs, 2017, 35(2), 180-188.
Kasinski, A.L.; Kelnar, K.; Stahlhut, C.; Orellana, E.; Zhao, J.; Shimer, E.; Dysart, S.; Chen, X.; Bader, A.G.; Slack, F.J. A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer. Oncogene, 2015, 34(27), 3547-3555.
Daige, C.L.; Wiggins, J.F.; Priddy, L.; Nelligan-Davis, T.; Zhao, J.; Brown, D. Systemic delivery of a miR-34a mimic as a potential therapeutic for liver cancer. Mol. Cancer Ther, 2014.molcanther. 0209.2014..
Tazawa, H.; Tsuchiya, N.; Izumiya, M.; Nakagama, H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc. Natl. Acad. Sci. USA, 2007, 104(39), 15472-15477.
Ottosen, S.; Parsley, T.B.; Yang, L.; Zeh, K.; van Doorn, L-J.; van der Veer, E.; Raney, A.K.; Hodges, M.R.; Patick, A.K. In vitro antiviral activity and preclinical and clinical resistance profile of miravirsen, a novel anti-hepatitis C virus therapeutic targeting the human factor miR-122. Antimicrob. Agents Chemother., 2015, 59(1), 599-608.
Chakraborty, C.; Sharma, A.R.; Sharma, G.; Doss, C.G.P.; Lee, S-S. Therapeutic miRNA and siRNA: Moving from bench to clinic as next generation medicine. Mol. Ther. Nucleic Acids, 2017, 8, 132-143.
Gebert, L.F.; Rebhan, M.A.; Crivelli, S.E.; Denzler, R.; Stoffel, M.; Hall, J. Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. Nucleic Acids Res., 2014, 42(1), 609-621.
Goyal, R.; Kapadia, C.H.; Melamed, J.R.; Riley, R.S.; Day, E.S. Layer-by-layer assembled gold nanoshells for the intracellular delivery of miR-34a. Cell. Mol. Bioeng., 2018, 11(5), 383-396.
He, Q.; Guo, S.; Qian, Z.; Chen, X. Development of individualized anti-metastasis strategies by engineering nanomedicines. Chem. Soc. Rev., 2015, 44(17), 6258-6286.
Cullis, P.R.; Hope, M.J. Lipid nanoparticle systems for enabling gene therapies. Mol. Ther., 2017, 25(7), 1467-1475.
Trang, P.; Wiggins, J.F.; Daige, C.L.; Cho, C.; Omotola, M.; Brown, D.; Weidhaas, J.B.; Bader, A.G.; Slack, F.J. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol. Ther., 2011, 19(6), 1116-1122.
Bravo, V.; Rosero, S.; Ricordi, C.; Pastori, R.L. Instability of miRNA and cDNAs derivatives in RNA preparations. Biochem. Biophys. Res. Commun., 2007, 353(4), 1052-1055.
Lovis, P.; Roggli, E.; Laybutt, D.R.; Gattesco, S.; Yang, J-Y.; Widmann, C.; Abderrahmani, A.; Regazzi, R. Alterations in microRNA expression contribute to fatty acid-induced pancreatic β-cell dysfunction. Diabetes, 2008, 57(10), 2728-2736.
Backe, M.B.; Novotny, G.W.; Christensen, D.P.; Grunnet, L.G.; Mandrup-Poulsen, T. Altering β-cell number through stable alteration of miR-21 and miR-34a expression. Islets, 2014, 6(1)e27754
Guengerich, F.P. Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS J., 2006, 8(1), E101-E111.
Khatsenko, O.; Morgan, R.; Truong, L.; York-Defalco, C.; Sasmor, H.; Conklin, B.; Geary, R.S. Absorption of antisense oligonucleotides in rat intestine: effect of chemistry and length. Antisense Nucleic Acid Drug Dev., 2000, 10(1), 35-44.
Stenvang, J.; Petri, A.; Lindow, M.; Obad, S.; Kauppinen, S. Inhibition of microRNA function by antimiR oligonucleotides. Silence, 2012, 3(1), 1.
Agostini, M.; Knight, R.A. miR-34: From bench to bedside. Oncotarget, 2014, 5(4), 872-881.
Eades, G.; Yao, Y.; Yang, M.; Zhang, Y.; Chumsri, S.; Zhou, Q. miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells. J. Biol. Chem., 2011, 286(29), 25992-26002.
Guo, X.; Wu, Y.; Hartley, R.S. MicroRNA-125a represses cell growth by targeting HuR in breast cancer. RNA Biol., 2009, 6(5), 575-583.
Shimono, Y.; Zabala, M.; Cho, R.W.; Lobo, N.; Dalerba, P.; Qian, D.; Diehn, M.; Liu, H.; Panula, S.P.; Chiao, E.; Dirbas, F.M.; Somlo, G.; Pera, R.A.; Lao, K.; Clarke, M.F. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell, 2009, 138(3), 592-603.
Wu, F.; Zhu, S.; Ding, Y.; Beck, W.T.; Mo, Y-Y. MicroRNA-mediated regulation of Ubc9 expression in cancer cells. Clin. Cancer Res., 2009, 15(5), 1550-1557.
Imani, S.; Zhang, X.; Hosseinifard, H.; Fu, S.; Fu, J. The diagnostic role of microRNA-34a in breast cancer: A systematic review and meta-analysis. Oncotarget, 2017, 8(14), 23177-23187.

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Year: 2019
Page: [665 - 673]
Pages: 9
DOI: 10.2174/1389201020666190617162042
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