Response to neoadjuvant chemotherapy in breast cancer: do microRNAs matter?

Springer Science and Business Media LLC - 2022
Dinara Ryspayeva1, V. Halytskiy2, Nazarii Kobyliak3, Iryna Dosenko1, А. В. Федосов3, M. Inomistova1, T. Drevytska4, Vitalyi Gurianov3, О. М. Сулаєва5
1Department of Oncohematology and Adjuvant Treatment Methods, National Cancer Institute, Lomonosova str, 33/43, Kyiv, 03022, Ukraine
2Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine, Kyiv, 01054, Ukraine
3Endocrinology Department, Bogomolets National Medical University, Kyiv, 01601, Ukraine
4Bogomolets Institute of Physiology of the National Academy of Sciences of Ukraine, Kyiv, 01024, Ukraine
5Medical Laboratory CSD, Kyiv, 03148, Ukraine

Tóm tắt

Abstract Background Conventionally, breast cancer (BC) prognosis and prediction of response to therapy are based on TNM staging, histological and molecular subtype, as well as genetic alterations. The role of various epigenetic factors has been elucidated in carcinogenesis. However, it is still unknown to what extent miRNAs affect the response to neoadjuvant chemotherapy (NACT). This pilot study is focused on evaluating the role of miR-34a, miR-124a, miR-155, miR-137 and miR-373 in response to NACT. Methods That was a prospective study enrolling 34 patients with histologically confirmed BC of II-III stages. The median age of patients was 53 (47–59.8) years old, 70.6% of whom were HR-positive. MiRs levels were measured in the primary tumor before and after NACT. The response to therapy was assessed after surgery using the Miller-Payne scoring system. To establish the role of miRs in modulating response to NACT the Cox model was applied for analysis. Results BC demonstrated a great variability of miRs expression before and after NACT with no strong links to tumor stage and molecular subtype. Only miR-124a and miR-373 demonstrated differential expression between malignant and normal breast tissues before and after therapy though these distinctions did not impact response to NACT. Besides miR-124a and miR-137 levels after NACT were found to be dependent on HR status. While miR-124a levels increased (p = 0.021) in the tumor tissue, the expression of miR-137 was downregulated (p = 0.041) after NACT in HR positive BC. Conclusions The study revealed differences in miR-124a and miR-373 expression after NACT in primary BC tissues. Although miRs levels did not impact the response to NACT, we found miR-124a and miR-137 levels to be related to hormonal sensitivity of BC.

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Tài liệu tham khảo

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7–33. https://doi.org/10.3322/CAAC.21654.

Kurozumi S, Yamaguchi Y, Kurosumi M, et al. Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes. J Hum Genet. 2017;62:15–24. https://doi.org/10.1038/JHG.2016.89.

Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8. https://doi.org/10.1038/NATURE03702.

Izumiya M, Tsuchiya N, Okamoto K, Nakagama H. Systematic exploration of cancer-associated microRNA through functional screening assays. Cancer Sci. 2011;102:1615–21. https://doi.org/10.1111/J.1349-7006.2011.02007.X.

Adi Harel S, Bossel Ben-Moshe N, Aylon Y, et al. Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth. Cell Death Differ. 2015;22:1328–40. https://doi.org/10.1038/CDD.2014.221.

Yang L, Song X, Zhu J, et al. Tumor suppressor microRNA-34a inhibits cell migration and invasion by targeting MMP-2/MMP-9/FNDC3B in esophageal squamous cell carcinoma. Int J Oncol. 2017;51:378–88. https://doi.org/10.3892/ijo.2017.4015.

Lima CR, Gomes CC, Santos MF. Role of microRNAs in endocrine cancer metastasis. Mol Cell Endocrinol. 2017;456:62–75. https://doi.org/10.1016/J.MCE.2017.03.015.

Iorio MV, Ferracin M, Liu CG, et al. MicroRNA gene expression deregulation in human breast cancer. Can Res. 2005;65:7065–70. https://doi.org/10.1158/0008-5472.CAN-05-1783.

Ohzawa H, Miki A, Teratani T, et al. Usefulness of miRNA profiles for predicting pathological responses to neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer. Oncol Lett. 2017;13:1731–40. https://doi.org/10.3892/OL.2017.5628.

Blenkiron C, Goldstein LD, Thorne NP, et al. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol. 2007;8:R214. https://doi.org/10.1186/GB-2007-8-10-R214.

Alma DCP, Gerardo CM, Abraham PT, et al. Micro-RNAs as potential predictors of response to breast cancer systemic therapy: future clinical implications. Int J Mol Sci. 2017;18:1182. https://doi.org/10.3390/IJMS18061182.

Takahashi RU, Miyazaki H, Ochiya T. The roles of microRNAs in breast cancer. Cancers. 2015;7:598–616. https://doi.org/10.3390/CANCERS7020598.

Kolacinska A, Morawiec J, Fendler W, et al. Association of microRNAs and pathologic response to preoperative chemotherapy in triple negative breast cancer: preliminary report. Mol Biol Rep. 2014;41:2851–7. https://doi.org/10.1007/S11033-014-3140-7.

Negrini M, Nicoloso MS, Calin GA. MicroRNAs and cancer–new paradigms in molecular oncology. Curr Opin Cell Biol. 2009;21:470–9. https://doi.org/10.1016/J.CEB.2009.03.002.

Kastl L, Brown I, Schofield AC. miRNA-34a is associated with docetaxel resistance in human breast cancer cells. Breast Cancer Res Treat. 2012;131:445–54. https://doi.org/10.1007/S10549-011-1424-3.

Peurala H, Greco D, Heikkinen T, et al. MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer. PLoS ONE. 2011;6: e26122. https://doi.org/10.1371/JOURNAL.PONE.0026122.

Eichelser C, Flesch-Janys D, Chang-Claude J, et al. Deregulated serum concentrations of circulating cell-free microRNAs miR-17, miR-34a, miR-155, and miR-373 in human breast cancer development and progression. Clin Chem. 2013;59:1489–96. https://doi.org/10.1373/CLINCHEM.2013.205161.

Tokumaru Y, Eriko K, Oshi M, et al. High expression of miR-34a associated with less aggressive cancer biology but not with survival in breast cancer. Int J Mol Sci. 2020;21:3045. https://doi.org/10.3390/IJMS21093045.

Chen F, Luo N, Hu Y, et al. MiR-137 suppresses triple-negative breast cancer stemness and tumorigenesis by perturbing BCL11A-DNMT1 Interaction. Cell Physiol Biochem. 2018;47:2147–58. https://doi.org/10.1159/000491526.

Lee SJ, Jeong JH, Kang SH, et al. MicroRNA-137 inhibits cancer progression by targeting Del-1 in triple-negative breast cancer cells. Int J Mol Sci. 2019;20:6162. https://doi.org/10.3390/IJMS20246162.

Ying X, Sun Y, He P. MicroRNA-137 inhibits BMP7 to enhance the epithelial-mesenchymal transition of breast cancer cells. Oncotarget. 2017;8:18348–58. https://doi.org/10.18632/ONCOTARGET.15442.

Hafez MM, Hassan ZK, Zekri ARN, et al. MicroRNAs and metastasis-related gene expression in Egyptian breast cancer patients. Asian Pac J Cancer Prev. 2012;13:591–8. https://doi.org/10.7314/APJCP.2012.13.2.591.

Kong W, He L, Richards EJ, et al. Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene. 2014;33:679–89. https://doi.org/10.1038/ONC.2012.636.

Farsinejad S, Rahaie M, Alizadeh AM, et al. Expression of the circulating and the tissue microRNAs after surgery, chemotherapy, and radiotherapy in mice mammary tumor. Tumour Biol. 2016;37:14225–34. https://doi.org/10.1007/S13277-016-5292-7.

Gasparini P, Lovat F, Fassan M, et al. Protective role of miR-155 in breast cancer through RAD51 targeting impairs homologous recombination after irradiation. Proc Natl Acad Sci USA. 2014;111:4536–41. https://doi.org/10.1073/PNAS.1402604111.

Huang Q, Gumireddy K, Schrier M, et al. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol. 2008;10:202–10. https://doi.org/10.1038/NCB1681.

Jing SY, Jing SQ, Liu LL, et al. Down-expression of miR-373 predicts poor prognosis of glioma and could be a potential therapeutic target. Eur Rev Med Pharmacol Sci. 2017;21:2421–5.

Nakata K, Ohuchida K, Mizumoto K, et al. Micro RNA-373 is down-regulated in pancreatic cancer and inhibits cancer cell invasion. Ann Surg Oncol. 2014;21(Suppl 4):564–74. https://doi.org/10.1245/S10434-014-3676-8.

Qu Y, Liu H, Zheng L, et al. Effects of microRNA-373 on the proliferation and invasiveness of breast carcinoma and its mechanisms. Zhonghua Yi Xue Za Zhi. 2017;97:603–7. https://doi.org/10.3760/CMA.J.ISSN.0376-2491.2017.08.009.

Crosby ME, Kulshreshtha R, Ivan M, Glazer PM. MicroRNA regulation of DNA repair gene expression in hypoxic stress. Can Res. 2009;69:1221–9. https://doi.org/10.1158/0008-5472.CAN-08-2516.

Kofman AV, Kim J, Park SY, et al. microRNA-34a promotes DNA damage and mitotic catastrophe. Cell Cycle. 2013;12:3500–11. https://doi.org/10.4161/CC.26459.

Czochor JR, Sulkowski P, Glazer PM. miR-155 overexpression promotes genomic instability by reducing high-fidelity polymerase delta expression and activating error-prone DSB repair. Mol Cancer Res. 2016;14:363–73. https://doi.org/10.1158/1541-7786.MCR-15-0399.

Ryspayeva D, Lyashenko A, Dosenko I, et al. Predictive factors of pathological response to neoadjuvant chemotherapy in patients with breast cancer. JBUON. 2020;25:168–75.

Wang L, Asirvatham JR, Ma Y, et al. HER-2/neu-positive breast cancer neoadjuvant chemotherapy response after implementation of 2018 ASCO/CAP focused update. Breast J. 2021;27:631–7. https://doi.org/10.1111/TBJ.14241.

Ogston KN, Miller ID, Payne S, et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003;12:320–7. https://doi.org/10.1016/S0960-9776(03)00106-1.

Wei F, Cao C, Xu X, Wang J. Diverse functions of miR-373 in cancer. J Transl Med. 2015;13:162. https://doi.org/10.1186/S12967-015-0523-Z.

Wang LQ, Yu P, Li B, et al. miR-372 and miR-373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways. Mol Oncol. 2018;12:1949–64. https://doi.org/10.1002/1878-0261.12376.

Zhou AD, Diao LT, Xu H, et al. β-Catenin/LEF1 transactivates the microRNA-371–373 cluster that modulates the Wnt/β-catenin-signaling pathway. Oncogene. 2012;31:2968–78. https://doi.org/10.1038/onc.2011.461.

Peng Y, Zhang X, Feng X, et al. The crosstalk between microRNAs and the Wnt/β-catenin signaling pathway in cancer. Oncotarget. 2017;8:14089–106. https://doi.org/10.18632/ONCOTARGET.12923.

Chen D, Dang BL, Huang JZ, et al. MiR-373 drives the epithelial-to-mesenchymal transition and metastasis via the miR-373-TXNIP-HIF1α-TWIST signaling axis in breast cancer. Oncotarget. 2015;6:32701–12. https://doi.org/10.18632/ONCOTARGET.4702.

Weng J, Zhang H, Wang C, et al. miR-373-3p targets DKK1 to promote EMT-induced metastasis via the Wnt/ β-catenin pathway in tongue squamous cell carcinoma. Biomed Res Int. 2017;2017:6010926. https://doi.org/10.1155/2017/6010926.

Tessitore A, Cicciarelli G, Del Vecchio F, et al. MicroRNAs in the DNA damage/repair network and cancer. Int J Genomics. 2014;2014: 820248. https://doi.org/10.1155/2014/820248.

Han ZB, Yang Z, Chi Y, et al. MicroRNA-124 suppresses breast cancer cell growth and motility by targeting CD151. Cell Physiol Biochem. 2013;31:823–32. https://doi.org/10.1159/000350100.

Chen Z, Liu S, Tian L, et al. miR-124 and miR-506 inhibit colorectal cancer progression by targeting DNMT3B and DNMT1. Oncotarget. 2015;6:38139–50. https://doi.org/10.18632/ONCOTARGET.5709.

Yang Q, Wan L, Xiao C, et al. Inhibition of LHX2 by miR-124 suppresses cellular migration and invasion in non-small cell lung cancer. Oncol Lett. 2017;14:3429–36. https://doi.org/10.3892/OL.2017.6607.

Jiang CF, Li DM, Shi ZM, et al. Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis. Oncotarget. 2016;7:36940–55. https://doi.org/10.18632/ONCOTARGET.9230.

Zhou Z, Lv J, Wang J, et al. Role of microRNA-124 as a prognostic factor in multiple neoplasms: a meta-analysis. Dis Markers. 2019;2019:1654780. https://doi.org/10.1155/2019/1654780.

Dong LL, Chen LM, Wang WM, Zhang LM. Decreased expression of microRNA-124 is an independent unfavorable prognostic factor for patients with breast cancer. Diagn Pathol. 2015;10:45. https://doi.org/10.1186/S13000-015-0257-5.

Zhang L, Chen X, Liu B, Han J. MicroRNA-124-3p directly targets PDCD6 to inhibit metastasis in breast cancer. Oncol Lett. 2018;15:984–90. https://doi.org/10.3892/OL.2017.7358.

Liu C, Xing H, Guo C, et al. MiR-124 reversed the doxorubicin resistance of breast cancer stem cells through STAT3/HIF-1 signaling pathways. Cell Cycle. 2019;18:2215–27. https://doi.org/10.1080/15384101.2019.1638182.

Bi WP, Xia M, Wang XJ. miR-137 suppresses proliferation, migration and invasion of colon cancer cell lines by targeting TCF4. Oncol Lett. 2018;15:8744–8. https://doi.org/10.3892/OL.2018.8364.

Zhao Y, Li Y, Lou G, et al. MiR-137 targets estrogen-related receptor alpha and impairs the proliferative and migratory capacity of breast cancer cells. PLoS ONE. 2012;7: e39102. https://doi.org/10.1371/JOURNAL.PONE.0039102.

Onyido EK, Sweeney E, Nateri AS. Wnt-signalling pathways and microRNAs network in carcinogenesis: experimental and bioinformatics approaches. Mol Cancer. 2016;15:56. https://doi.org/10.1186/S12943-016-0541-3.

Menck K, Heinrichs S, Wlochowitz D, et al. WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer. J Exp Clin Cancer Res. 2021;40:395. https://doi.org/10.1186/S13046-021-02187-Z/FIGURES/6.

Koni M, Pinnarò V, Brizzi MF. The Wnt signalling pathway: a tailored target in cancer. Int J Mol Sci. 2020;21:7697. https://doi.org/10.3390/IJMS21207697.

Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014. https://doi.org/10.1126/SCISIGNAL.2005189.

Caldon CE. Estrogen signaling and the DNA damage response in hormone dependent breast cancers. Front Oncol. 2014;4:106. https://doi.org/10.3389/FONC.2014.00106/BIBTEX.

Jiménez-Salazar JE, Damian-Ferrara R, Arteaga M, et al. Non-Genomic actions of estrogens on the DNA repair pathways are associated with chemotherapy resistance in breast cancer. Front Oncol. 2021;11: 631007. https://doi.org/10.3389/FONC.2021.631007.

Jansson MD, Lund AH. MicroRNA and cancer. Mol Oncol. 2012;6:590–610. https://doi.org/10.1016/J.MOLONC.2012.09.006.

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