Brain metastasis-related microRNAs in patients with advanced breast cancer

Autoři: Jun Sato aff001;  Akihiko Shimomura aff001;  Junpei Kawauchi aff002;  Juntaro Matsuzaki aff003;  Yusuke Yamamoto aff003;  Satoko Takizawa aff002;  Hiromi Sakamoto aff004;  Makoto Ohno aff005;  Yoshitaka Narita aff005;  Takahiro Ochiya aff003;  Kenji Tamura aff001
Působiště autorů: Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan aff001;  Toray Industries, Inc., Kanagawa, Japan aff002;  Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan aff003;  Department of Biobank and Tissue Resources, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Tokyo, Japan aff004;  Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan aff005;  Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan aff006
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


Brain metastasis is a major distant metastasis occurring in patients with advanced breast cancer, and is associated with poor prognosis. MicroRNAs (miRNAs) have a strong influence on various oncological functions and have been reported as potential biomarkers for detecting distant metastasis. Specific biomarkers and unique miRNAs for brain metastasis have yet to be reported. The aim of this study was to identify novel miRNAs in serum, to assist in the diagnosis of brain metastasis in patients with advanced breast cancer. We retrospectively analyzed the medical records of patients with breast cancer and collected clinical data. In addition, we evaluated serum miRNA profiles in patients with breast cancer, with and without brain metastasis, using high-sensitivity microarrays. All patients underwent computed tomography or magnetic resonance imaging brain imaging tests. A total of 51 serum samples from patients with breast cancer and brain metastasis, stored in the National Cancer Center Biobank, were used, and 28 serum samples were obtained from controls without brain metastasis. Two miRNAs, miR-4428 and miR-4480, could significantly distinguish patients with brain metastasis, with area under the receiver operating characteristic curve (AUC) values of 0.779 and 0.781, respectively, while a combination of miR-4428 and progesterone receptor had an AUC value of 0.884. No significant correlations were identified between the expression levels of these two miRNAs in serum and clinical data. We conclude that serum miR-4428 and miR-4480 may be useful as biomarkers for predicting brain metastasis in patients with breast cancer.

Klíčová slova:

Biomarkers – Breast cancer – Cancer detection and diagnosis – Cancer treatment – Metastasis – Microarrays – MicroRNAs – Brain metastasis


1. Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28: 3271–3277. doi: 10.1200/JCO.2009.25.9820 20498394

2. Rostami R, Mittal S, Rostami P, Tavassoli F, Jabbari B. Brain metastasis in breast cancer: a comprehensive literature review. J Neurooncol. 2016;127: 407–414. doi: 10.1007/s11060-016-2075-3 26909695

3. Bondy ML, Hortobagyi GN, Rivera E, Mirza NQ, Broglio K, Altundag K, et al. Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis. Cancer. 2007;110: 2640–2647. doi: 10.1002/cncr.23088 17960791

4. Weissman DE. Glucocorticoid treatment for brain metastases and epidural spinal cord compression: A review. J Clin Oncol. 1988;6: 543–551. doi: 10.1200/JCO.1988.6.3.543 3280744

5. Shioura H, Toyoda T, Oya N, Kenjyo M, Hayakawa K, Inomata T, et al. Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases. Jama. 2006;295: 2483. doi: 10.1001/jama.295.21.2483 16757720

6. Bachelot T, Romieu G, Campone M, Diéras V, Cropet C, Dalenc F, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): A single-group phase 2 study. Lancet Oncol. 2013;14: 64–71. doi: 10.1016/S1470-2045(12)70432-1 23122784

7. Winer EP, Roychowdhury D, Wardley A, Oliva C, Greil R, Yardley D, et al. Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer. Clin Cancer Res. 2009;15: 1452–1459. doi: 10.1158/1078-0432.CCR-08-1080 19228746

8. Zhang B, Pan X, Cobb GP AT. MicroRNAs as Oncogenes and Tumor Suppressors. Dev Biol. 2007;302: 1–12. doi: 10.1016/j.ydbio.2006.08.028 16989803

9. Zhu W, Qin W, Atasoy U, Sauter ER. Circulating microRNAs in breast cancer and healthy subjects. BMC Res Notes. 2009;2: 1–5. doi: 10.1186/1756-0500-2-1

10. Kerin MJ, Miller N, Kelly R, Newell J, Heneghan HM. Systemic miRNA-195 Differentiates Breast Cancer from Other Malignancies and Is a Potential Biomarker for Detecting Noninvasive and Early Stage Disease. Oncologist. 2010;15: 673–682. doi: 10.1634/theoncologist.2010-0103 20576643

11. Asaga S, Kuo C, Nguyen T, Terpenning M, Giuliano AE HD. Direct Serum Assay for MicroRNA-21 Concentrations in Early and Advanced Breast Cancer. Clin Chem. 2011;57: 84–91. doi: 10.1373/clinchem.2010.151845 21036945

12. Roth C, Rack B, Müller V, Janni W, Pantel K SH. Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Res. 2010;12: 6–13. doi: 10.1186/bcr2766 21047409

13. Jung EJ, Santarpia L, Kim J, Esteva FJ, Moretti E, Buzdar AU, Di Leo A, Le XF, Bast RC Jr, Park ST, Pusztai L CG. Plasma microRNA 210 levels correlate with sensitivity to trastuzumab and tumor presence in breast cancer patients. Cancer. 2012;118: 2603–2614. doi: 10.1002/cncr.26565 22370716

14. Si H, Sun X, Chen Y, Cao Y, Chen S, Wang H HC. Circulating microRNA-92a and microRNA-21 as novel minimally invasive biomarkers for primary breast cancer. J Cancer Res Clin Oncol. 2013;139: 223–229. doi: 10.1007/s00432-012-1315-y 23052693

15. Sun Y, Wang M, Lin G, Sun S, Li X, Qi J, et al. Serum MicroRNA-155 as a Potential Biomarker to Track Disease in Breast Cancer. PLoS One. 2012;7: 1–8. doi: 10.1371/journal.pone.0047003 23071695

16. Chan M, Liaw CS, Ji SM, Tan HH, Wong CY, Thike AA, et al. Identification of circulating microRNA signatures for breast cancer detection. Clin Cancer Res. 2013;19: 4477–4487. doi: 10.1158/1078-0432.CCR-12-3401 23797906

17. Cuk K, Zucknick M, Madhavan D, Schott S, Golatta M, Heil J, et al. Plasma MicroRNA Panel for Minimally Invasive Detection of Breast Cancer. PLoS One. 2013;8: e76729. doi: 10.1371/journal.pone.0076729 24194846

18. Zearo S, Kim E, Zhu Y, Zhao JT, Sidhu SB, Robinson BG SPs. MicroRNA-484 is more highly expressed in serum of early breast cancer patients compared to healthy volunteers. BMC Cancer. 2014;14: 1–7. doi: 10.1186/1471-2407-14-1

19. Sochor M, Basova P, Pesta M, Dusilkova N, Bartos J, Burda P, et al. Oncogenic microRNAs: miR-155, miR-19a, miR-181b, and miR-24 enable monitoring of early breast cancer in serum. BMC Cancer. 2014;14: 448. doi: 10.1186/1471-2407-14-448 24938880

20. Shen J, Hu Q, Schrauder M, Yan L, Wang D, Medico L, Guo Y, Yao S, Zhu Q, Liu B, Qin M, Beckmann MW, Fasching PA, Strick R, Johnson CS, Ambrosone CB, Zhao H LS. Circulating miR-148b and miR-133a as biomarkers for breast cancer detection. Oncotarget. 2014;5: 5284–94. doi: 10.18632/oncotarget.2014 25051376

21. Shimomura A, Shiino S, Kawauchi J, Takizawa S, Sakamoto H, Matsuzaki J, Ono M, Takeshita F, Niida S, Shimizu C, Fujiwara Y, Kinoshita T, Tamura K OT. Novel combination of serum microRNA for detecting breast cancer in the early stage. Cancer Sci. 2016;107: 326–334. doi: 10.1111/cas.12880 26749252

22. Schrijver WAME, van Diest PJ, Moelans CB. Unravelling site-specific breast cancer metastasis: A microRNA expression profiling study. Oncotarget. 2017;8: 3111–3123. doi: 10.18632/oncotarget.13623 27902972

23. Okuda H, Xing F, Pandey PR, Sharma S, Watabe M, Pai SK, Mo YY, Iiizumi-Gairani M, Hirota S, Liu Y, Wu K, Pochampally R WK. miR-7 Suppresses Brain Metastasis of Breast Cancer Stem-Like Cells By Modulating KLF4. Cancer Res. 2013;73: 1434–1444. doi: 10.1158/0008-5472.CAN-12-2037 23384942

24. Zhang L, Sullivan PS, Goodman JC, Gunaratne PH, Marchetti D. MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase. Cancer Res. 2011;71: 645–654. doi: 10.1158/0008-5472.CAN-10-1910 21266359

25. Xing F, Sharma S, Liu Y, Mo YY, Wu K, Zhang YY, et al. MiR-509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF-α. Oncogene. 2015;34: 4890–4900. doi: 10.1038/onc.2014.412 25659578

26. Ahmad A, Ginnebaugh KR, Sethi S, Chen W, Ali R, Mittal S, et al. miR-20b is up-regulated in brain metastases from primary breast cancers. Oncotarget. 2015;6: 12188–12195. doi: 10.18632/oncotarget.3664 25893380

27. Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, et al. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun. 2015;6: 6716. doi: 10.1038/ncomms7716 25828099

28. Shui Y, Yu X, Duan R, Bao Q, Wu J, Yuan H, et al. miR-130b-3p inhibits cell invasion and migration by targeting the Notch ligand Delta-like 1 in breast carcinoma. Gene. 2017;609: 80–87. doi: 10.1016/j.gene.2017.01.036 28163094

29. Montano M. MicroRNAs: miRRORS of Health and Disease. Transl Res. 2011;157: 157–162. doi: 10.1016/j.trsl.2011.02.001 21420026

30. Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast. J Clin Oncol. 2013;31: 3997–4013. doi: 10.1200/JCO.2013.50.9984 24101045

31. Spector Y, Chajut A, Rosenwald S, Aharonov R, Mueller WC, Jaeger D, et al. Accurate Classification of Metastatic Brain Tumors Using a Novel MicroRNA-Based Test. Oncologist. 2011;16: 165–174. doi: 10.1634/theoncologist.2010-0305 21273512

32. McDermott R, Gabikian P, Sarvaiya P, Ulasov I, Lesniak MS. MicroRNAs in brain metastases: Big things come in small packages. J Mol Med. 2013;91: 5–13. doi: 10.1007/s00109-012-0971-3 23138927

33. Alsidawi S, Malek E, Driscoll JJ. MicroRNAs in brain metastases: Potential role as diagnostics and therapeutics. Int J Mol Sci. 2014;15: 10508–10526. doi: 10.3390/ijms150610508 24921708

34. Popp NA, Yu D, Green B, Chew EY, Ning B, Chan CC TJ. Functional single nucleotide polymorphism in IL-17A 3’ untranslated region is targeted by miR-4480 in vitro and may be associated with age-related macular degeneration. Environ Mol Mutagen. 2016;57: 58–64. doi: 10.1002/em.21982 26765636

35. Ridgway LD, Wetzel MD, Ngo JA, Erdreich-Epstein A, Marchetti D. Heparanase-Induced GEF-H1 Signaling Regulates the Cytoskeletal Dynamics of Brain Metastatic Breast Cancer Cells. Mol Cancer Res. 2012;10: 689–702. doi: 10.1158/1541-7786.MCR-11-0534 22513363

36. Baffa R, Fassan M, Volinia S, O’Hara B, Liu CG, Palazzo JP, Gardiman M, Rugge M, Gomella LG, Croce CM RA. MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J Pathol. 2009;219: 214–21. doi: 10.1002/path.2586 19593777

37. Haider MT, Taipaleenmäki H. Targeting the metastatic bone microenvironment by MicroRNAs. Front Endocrinol (Lausanne). 2018;9: 202. doi: 10.3389/fendo.2018.00202 29780354

38. Taipaleenmäki H, Browne G, Akech J, Zustin J, Van Wijnen AJ, Stein JL, et al. Targeting of Runx2 by miR-135 and miR-203 impairs progression of breast cancer and metastatic bone disease. Cancer Res. 2015;75: 1433–1444. doi: 10.1158/0008-5472.CAN-14-1026 25634212

39. Hassan MQ, Maeda Y, Taipaleenmaki H, Zhang W, Jafferji M, Gordon JAR, et al. miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. J Biol Chem. 2012;287: 42084–42092. doi: 10.1074/jbc.M112.377515 23060446

40. Zearo S, Kim E, Zhu Y, Zhao JT, Sidhu SB, Robinson BG, et al. MicroRNA-484 is more highly expressed in serum of early breast cancer patients compared to healthy volunteers. BMC Cancer. 2014;14: 1–7. doi: 10.1186/1471-2407-14-1

41. Custódio-Santos T, Videira M, Brito MA. Brain metastasization of breast cancer. Biochim Biophys Acta—Rev Cancer. 2017;1868: 132–147. doi: 10.1016/j.bbcan.2017.03.004 28341420

42. Janssen EAM, Slewa A, Gudlaugsson E, Jonsdottir K, Skaland I, Søiland H, et al. Biologic profiling of lymph node negative breast cancers by means of microRNA expression. Mod Pathol. 2010;23: 1567–1576. doi: 10.1038/modpathol.2010.177 20818337

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