Assessment of correlation between Trastuzumab resistance and miR-885-3p relative expression in the BT-474 Human Breast Cancer Cell Line

Document Type : Original Article

Authors

1 Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran

2 Cellular and Molecular Research Center, Birjand University of Medical Sciences , Birjnad. Iran

Abstract

Trastuzumab has been applied widely in the treatment of breast cancer. The majority of initial responders display disease progression again within one year. Regardless of the high resistance rate, the molecular mechanisms affected this disease are not well understood. MicroRNAs are small, non-coding RNA molecules that involved in gene regulation. There is evidence that promotes miRNAs as potential candidates to mediate therapeutic actions by targeting genes involved in drug response. The purpose of this study is to evaluate miR-885-3p in HER2 positive breast cancer chemoresistance. Trastuzumab-resistant BT-474 cells were generated by in vitro culture of BT-474 cells continuously in the presence of trastuzumab about 9 months. The relative expression of miR-885-3p to U6 RNA was evaluated in trastuzumab-resistant and sensitive cells using Relative Real-Time PCR. The Mann-Whitney test is used to compare the differences between the two groups. The MTT assay showed that BT-474 breast cancer cells were resistant to this drug under long-term culturing with trastuzumab (p < 0.05). MiR-885-3p expression was also significantly downregulated in trastuzumab-resistant cells in comparison with the parent cells (p < 0.05).:  As the relative expression of candidate microRNAs was statistically different in trastuzumab-resistant and sensitive cells, we hypothesize that miR-885-3p downregulation as a possible mechanism of trastuzumab resistance.

Keywords


1.      Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. (2011).Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 9:16–32.
 
2.      Loi S, de Azambuja E, Pugliano L, Sotiriou C, Piccart MJ. (2011). HER2-overexpressing breast cancer: time for the cure with less chemotherapy? Curr Opin Oncol. 23:547–558.
 
3.      Rexer BN, Arteaga CL. (2012). Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog. 17:1–16.
 
4.      Parra-Palau JL, Morancho B, Peg V, Escorihuela M, Scaltriti M, Vicario R, Zacarias-Fluck M, Pedersen K, Pandiella A, Nuciforo P, Serra V, Cortés J, Baselga J, et al. (2014). Effect of p95HER2/611CTF on the response to trastuzumab and chemotherapy. J Natl Cancer Inst. 106. pii: dju291.
 
5.      Pohlmann PR, Mayer IA, Mernaugh R. (2009). Resistance to Trastuzumab in Breast Cancer. Clin Cancer Res. 15:7479–7491.
 
6.      Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D. (2004). PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 6:117–127.
 
7.      Rexer BN, Shyr Y, Arteaga CL. (2013). Phosphatase and tensin homolog deficiency and resistance to trastuzumab and chemotherapy. J Clin Oncol. 2013; 31:2073–2075.
 
8.      Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN, et al. (2011). Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med. 17:461–469
 
9.      Esquela-Kerscher A, Slack FJ. (2006). Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 6(4):259–269. doi: 10.1038/nrc1840.
 
10.  Zhu X, Fu C, Zhang L, Xu G, Wang S. (2015). MiRNAs associated polymorphisms in the 3’UTR of MET promote the risk of non-small cell lung cancer. Cell Physiol Biochem; 37: 1159-1167.
 
11.  Xie T, Huang M, Wang Y, Wang L, Chen C, Chu X.(2016).  MicroRNAs as Regulators, Biomarkers and Therapeutic Targets in the Drug Resistance of Colorectal Cancer. Cell Physiol Biochem  40: 62-76.
 
12.  Robertson NM, Yigit MV. (2014). The role of microRNA in resistance to breast cancer therapy. Wiley Interdiscip Rev RNA.5: 823-833.
 
13.  Xu K, Liang X, Shen K, Sun L, Cui D, Zhao Y, Tian J, Ni L, Liu J. (2012) MiR-222 modulates multidrug resistance in human colorectal carcinoma by down-regulating ADAM-17. Exp Cell Res. 318: 2168-2177.
 
14.  Liu K, Liu S, Zhang W, Ji B, Wang Y, Liu Y.(2014) miR222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma. Int J Oncol. 45: 1537-1546
 
15.  Jung EJ, Santarpia L, Kim J, Esteva FJ, Moretti E, Buzdar AU, Di Leo A, Le XF, Bast RC Jr, Park ST, Pusztai L, Calin GA. (2012). Plasma microRNA 210 levels correlate with sensitivity to trastuzumab and tumor presence in breast cancer patients. Cancer.118: 2603-2614.
 
16.  Bai T, Dong DS, Pei L. (2014). Synergistic antitumor activity of resveratrol and miR-200c in human lung cancer. Oncol Rep. 31(5):2293–2297.
 
17.  Gong C, Yao Y, Wang Y, Liu B, Wu W, Chen J, Su F, Yao H, Song E. (2011). Up-regulation of miR-21 mediates resistance to trastuzumab therapy for breast cancer. J Biol Chem. 286(21):19127–19137.
 
18.  Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, Reiss M, Au JL, Haffty BG, Kang Y. (2009).  MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 15(1):9–20. doi: 10.1016/j.ccr.2008.11.013.
 
19.  Morris PG, McArthur HL, Hudis CA. (2009). Therapeutic options for metastatic breast cancer. Expert Opin Pharmacother. 10(6):967–981. doi: 10.1517/14656560902834961.
 
20.  Rexer, B. N. & Arteaga, C. L. (2012). Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog 17, 1–16
 
21.  Sato, F. et al. (2011). MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan Criteria. PLoS One 6, e16435, doi: 10.1371/journal.pone.0016435.
 
22.  Kastl, L., Brown, I. & Schofield, A. C. (2012). miRNA-34a is associated with docetaxel resistance in human breast cancer cells. Breast Cancer Res Treat 131, 445–454, doi: 10.1007/s10549-011-1424-3.
 
23.  Qian, B. et al. (2009). High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-beta1. Breast Cancer Res Treat 117, 131–140, doi: 10.1007/s10549-008-0219-7.
 
24.  Ichikawa T, Sato F, Terasawa K, Tsuchiya S, Toi M, Tsujimoto G, Shimizu K. (2012).  Trastuzumab produces therapeutic actions by upregulating miR-26a and miR-30b in breast cancer cells. PLoS One 7, e31422, doi: 10.1371/journal.pone.0031422.
 
25.  Le XF, Almeida MI, Mao W, Spizzo R, Rossi S, Nicoloso MS, Zhang S, Wu Y, Calin GA, Bast RC Jr. (2012). Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer. PLoS One. 7(7):e41170. doi: 10.1371/journal.pone.0041170.