Coordinated Rise of miR-155-5p and Regulatory T Cells in Peripheral Blood Mononuclear Cells: An Early Event in Newly Diagnosed Breast Cancer Pathogenesis
Abstract
miR-155-5p is a well-established oncomiR upregulated in a variety of human malignancies, including breast cancer, where its aberrant expression has been documented in both tumor tissue and serum. Given its role as a key modulator of immune-inflammatory pathways and regulatory T cell (Treg) expansion, we aimed to investigate its expression in the peripheral blood mononuclear cells (PBMCs) of breast cancer patients.
This study enrolled sixty (n=60) breast cancer patients and forty (n=40) age-matched healthy controls. The relative expression of miR-155-5p in PBMCs was quantified using qPCR, and Treg cell frequency (defined as CD4⁺CD25⁺Foxp3⁺) was assessed by flow cytometry.
The expression of miR-155 was significantly increased in PBMCs of breast cancer patients compared with that of the control group, especially in patients with high tumor grade. The number of Treg cells was also increased in PBMCs of patients than in the healthy group, however, no significant correlation was found between the expression levels of miR-155 and Treg cell count (r=-0.16).
Our findings demonstrate a significant up-regulation of miR-155-5p and a concomitant increase in Treg frequency in breast cancer patients, suggesting its potential role in shaping an immunosuppressive microenvironment. Consequently, miR-155-5p emerges as a promising non-invasive prognostic biomarker, warranting further validation in larger studies.
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2. Laronga C, Chagpar A, Vora S. Patient education: breast cancer guide to diagnosis and treatment (beyond the basics). UpToDate. Waltham. 2016.
3. Majid S, Rydén L, Manjer J. Predictive factors for sentinel node metastases in primary invasive breast cancer: a population-based cohort study of 2552 consecutive patients. World J Surg Oncol. 2018;16(1):54.
4. Niell BL, Freer PE, Weinfurtner RJ, Arleo EK, Drukteinis JS. Screening for breast cancer. Radiol Clin North Am. 2017;55(6):1145-62.
5. Zafar A, Khatoon S, Khan MJ, Abu J, Naeem A. Advancements and limitations in traditional anti-cancer therapies: a comprehensive review of surgery, chemotherapy, radiation therapy, and hormonal therapy. Discov Oncol. 2025;16(1):607.
6. Toss A, Venturelli M, Peterle C, Piacentini F, Cascinu S, Cortesi L. Molecular biomarkers for prediction of targeted therapy response in metastatic breast cancer: trick or treat? Int J Mol Sci. 2017;18(1):85.
7. Kitagawa M, Kitagawa K, Kotake Y, Niida H, Ohhata T. Cell cycle regulation by long non-coding RNAs. Cell Mol Life Sci. 2013;70(24):4785-94.
8. Crippa S, Cassano M, Sampaolesi M. Role of miRNAs in muscle stem cell biology: proliferation, differentiation and death. Curr Pharm Des. 2012;18(13):1718-29.
9. Iorio MV, Croce CM. microRNA involvement in human cancer. Carcinogenesis. 2012;33(6):1126-33.
10. Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther. 2016;1(1):1-9.
11. Pellegrino L, Jacob J, Roca-Alonso L, Krell J, Castellano L, Frampton AE. Altered expression of the miRNA processing endoribonuclease Dicer has prognostic significance in human cancers. Expert Rev Anticancer Ther. 2013;13(1):21-7.
12. Slaby O, Svoboda M, Fabian P, et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 2007;72(5-6):397-402.
13. Zhou X, Zhao F, Wang Z-N, et al. Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation. Oncol Rep. 2012;27(2):447-54.
14. Chen Y, Song Y, Wang Z, et al. Altered expression of MiR-148a and MiR-152 in gastrointestinal cancers and its clinical significance. J Gastrointest Surg. 2010;14(7):1170-9.
15. Palmero EI, de Campos SGP, Campos M, et al. Mechanisms and role of microRNA deregulation in cancer onset and progression. Genet Mol Biol. 2011;34:363-70.
16. Wang W, Luo Y-p. MicroRNAs in breast cancer: oncogene and tumor suppressors with clinical potential. J Zhejiang Univ Sci B. 2015;16(1):18-31.
17. Corcoran C, Friel AM, Duffy MJ, Crown J, O'Driscoll L. Intracellular and extracellular microRNAs in breast cancer. Clin Chem. 2011;57(1):18-32.
18. Abdalla F, Singh B, Bhat HK. MicroRNAs and gene regulation in breast cancer. J Biochem Mol Toxicol. 2020;34(11):e22567.
19. Martínez P, Thanasoula M, Muñoz P, et al. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009;23(17):2060-75.
20. Dinami R, Ercolani C, Petti E, et al. miR-155 drives telomere fragility in human breast cancer by targeting TRF1. Cancer Res. 2014;74(15):4145-56.
21. Guo Z, Maki M, Ding R, Yang Y, Zhang B, Xiong L. Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci Rep. 2014;4(1):5150.
22. Mahesh G, Biswas R. MicroRNA-155: a master regulator of inflammation. J Interferon Cytokine Res. 2019;39(6):321-30.
23. Vannini I, Fanini F, Fabbri M. Emerging roles of microRNAs in cancer. Curr Opin Genet Dev. 2018;48:128-33.
24. Schjenken JE, Moldenhauer LM, Zhang B, et al. MicroRNA miR-155 is required for expansion of regulatory T cells to mediate robust pregnancy tolerance in mice. Mucosal Immunol. 2020;13(4):609-25.
25. Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E. Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol. 2009;182(5):2578-82.
26. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011;241(1):260-8.
27. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080-9.
28. Iranparast S, Tahmasebi-Birgani M, Motamedfar A, Amari A, Ghafourian M. Altered Expression Levels of MicroRNA-155 and SOCS-1 in Peripheral Blood Mononuclear Cells of Newly Diagnosed Breast Cancer Patients. Iran J Allergy Asthma Immunol. 2021:1-8.
29. Sanguinetti A, Santini D, Bonafè M, Taffurelli M, Avenia N. Interleukin-6 and pro inflammatory status in the breast tumor microenvironment. World J Surg Oncol. 2015;13(1):129.
30. Jiang S, Zhang H-W, Lu M-H, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010;70(8):3119-27.
31. Banno K, Iida M, Yanokura M, et al. MicroRNA in cervical cancer: OncomiRs and tumor suppressor miRs in diagnosis and treatment. ScientificWorldJournal. 2014;2014(1):178075.
32. Zhang C-M, Zhao J, Deng H-Y. MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1. J Biomed Sci. 2013;20(1):79.
33. Marsolier J, Pineau S, Medjkane S, et al. OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes. PLoS Pathog. 2013;9(4):e1003222.
34. Zhang C-M, Zhao J, Deng H-Y. MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1. J Biomed Sci. 2013;20(1):1-10.
35. Tang B, Xiao B, Liu Z, et al. Identification of MyD88 as a novel target of miR-155, involved in negative regulation of Helicobacter pylori-induced inflammation. FEBS Lett. 2010;584(8):1481-6.
36. Zheng X, Huang H, Liu J, Li M, Liu M, Luo T. Propofol attenuates inflammatory response in LPS-activated microglia by regulating the miR-155/SOCS1 pathway. Inflammation. 2018;41(1):11-9.
37. Jablonski KA, Gaudet AD, Amici SA, Popovich PG, Guerau-de-Arellano M. Control of the inflammatory macrophage transcriptional signature by miR-155. PLoS One. 2016;11(7):e0159724.
38. Sun Y, Wang M, Lin G, et al. Serum microRNA-155 as a potential biomarker to track disease in breast cancer. 2012.
39. Chernyy V, Pustylnyak V, Kozlov V, Gulyaeva L. Increased expression of miR-155 and miR-222 is associated with lymph node positive status. J Cancer. 2018;9(1):135.
40. Petrović N, Kolaković A, Stanković A, et al. miR-155 expression level changes might be associated with initial phases of breast cancer pathogenesis and lymph-node metastasis. Cancer Biomark. 2016;16(3):385-94.
41. Zare A, Alipoor B, Omrani MD, Zali MR, Alamdari NM, Ghaedi H. Decreased miR-155-5p, miR-15a, and miR-186 expression in gastric cancer is associated with advanced tumor grade and metastasis. Iran Biomed J. 2019;23(5):338.
42. Chen X, Oppenheim JJ. Resolving the identity myth: key markers of functional CD4+ FoxP3+ regulatory T cells. Int Immunopharmacol. 2011;11(10):1489-96.
43. Li C, Jiang P, Wei S, Xu X, Wang J. Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol Cancer. 2020;19(1):1-23.
44. Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, Okada M. Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother. 2009;58(3):441-7.
45. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373-80.
46. Liu W, Ouyang H, Zeng Q, Luo R, Lu G. Decreased Treg-derived miR-181a and miR-155 correlated with reduced number and function of Treg cells in allergic rhinitis children. Eur Arch Otorhinolaryngol. 2019;276(4):1089-94.
47. Blüml S, Bonelli M, Niederreiter B, et al. Essential role of microRNA‐155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum. 2011;63(5):1281-8.
48. Gao S, Wang Y, Wang M, et al. MicroRNA-155, induced by FOXP3 through transcriptional repression of BRCA1, is associated with tumor initiation in human breast cancer. Oncotarget. 2017;8(25):41451.
2. Laronga C, Chagpar A, Vora S. Patient education: breast cancer guide to diagnosis and treatment (beyond the basics). UpToDate. Waltham. 2016.
3. Majid S, Rydén L, Manjer J. Predictive factors for sentinel node metastases in primary invasive breast cancer: a population-based cohort study of 2552 consecutive patients. World J Surg Oncol. 2018;16(1):54.
4. Niell BL, Freer PE, Weinfurtner RJ, Arleo EK, Drukteinis JS. Screening for breast cancer. Radiol Clin North Am. 2017;55(6):1145-62.
5. Zafar A, Khatoon S, Khan MJ, Abu J, Naeem A. Advancements and limitations in traditional anti-cancer therapies: a comprehensive review of surgery, chemotherapy, radiation therapy, and hormonal therapy. Discov Oncol. 2025;16(1):607.
6. Toss A, Venturelli M, Peterle C, Piacentini F, Cascinu S, Cortesi L. Molecular biomarkers for prediction of targeted therapy response in metastatic breast cancer: trick or treat? Int J Mol Sci. 2017;18(1):85.
7. Kitagawa M, Kitagawa K, Kotake Y, Niida H, Ohhata T. Cell cycle regulation by long non-coding RNAs. Cell Mol Life Sci. 2013;70(24):4785-94.
8. Crippa S, Cassano M, Sampaolesi M. Role of miRNAs in muscle stem cell biology: proliferation, differentiation and death. Curr Pharm Des. 2012;18(13):1718-29.
9. Iorio MV, Croce CM. microRNA involvement in human cancer. Carcinogenesis. 2012;33(6):1126-33.
10. Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther. 2016;1(1):1-9.
11. Pellegrino L, Jacob J, Roca-Alonso L, Krell J, Castellano L, Frampton AE. Altered expression of the miRNA processing endoribonuclease Dicer has prognostic significance in human cancers. Expert Rev Anticancer Ther. 2013;13(1):21-7.
12. Slaby O, Svoboda M, Fabian P, et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 2007;72(5-6):397-402.
13. Zhou X, Zhao F, Wang Z-N, et al. Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation. Oncol Rep. 2012;27(2):447-54.
14. Chen Y, Song Y, Wang Z, et al. Altered expression of MiR-148a and MiR-152 in gastrointestinal cancers and its clinical significance. J Gastrointest Surg. 2010;14(7):1170-9.
15. Palmero EI, de Campos SGP, Campos M, et al. Mechanisms and role of microRNA deregulation in cancer onset and progression. Genet Mol Biol. 2011;34:363-70.
16. Wang W, Luo Y-p. MicroRNAs in breast cancer: oncogene and tumor suppressors with clinical potential. J Zhejiang Univ Sci B. 2015;16(1):18-31.
17. Corcoran C, Friel AM, Duffy MJ, Crown J, O'Driscoll L. Intracellular and extracellular microRNAs in breast cancer. Clin Chem. 2011;57(1):18-32.
18. Abdalla F, Singh B, Bhat HK. MicroRNAs and gene regulation in breast cancer. J Biochem Mol Toxicol. 2020;34(11):e22567.
19. Martínez P, Thanasoula M, Muñoz P, et al. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009;23(17):2060-75.
20. Dinami R, Ercolani C, Petti E, et al. miR-155 drives telomere fragility in human breast cancer by targeting TRF1. Cancer Res. 2014;74(15):4145-56.
21. Guo Z, Maki M, Ding R, Yang Y, Zhang B, Xiong L. Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci Rep. 2014;4(1):5150.
22. Mahesh G, Biswas R. MicroRNA-155: a master regulator of inflammation. J Interferon Cytokine Res. 2019;39(6):321-30.
23. Vannini I, Fanini F, Fabbri M. Emerging roles of microRNAs in cancer. Curr Opin Genet Dev. 2018;48:128-33.
24. Schjenken JE, Moldenhauer LM, Zhang B, et al. MicroRNA miR-155 is required for expansion of regulatory T cells to mediate robust pregnancy tolerance in mice. Mucosal Immunol. 2020;13(4):609-25.
25. Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E. Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol. 2009;182(5):2578-82.
26. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011;241(1):260-8.
27. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080-9.
28. Iranparast S, Tahmasebi-Birgani M, Motamedfar A, Amari A, Ghafourian M. Altered Expression Levels of MicroRNA-155 and SOCS-1 in Peripheral Blood Mononuclear Cells of Newly Diagnosed Breast Cancer Patients. Iran J Allergy Asthma Immunol. 2021:1-8.
29. Sanguinetti A, Santini D, Bonafè M, Taffurelli M, Avenia N. Interleukin-6 and pro inflammatory status in the breast tumor microenvironment. World J Surg Oncol. 2015;13(1):129.
30. Jiang S, Zhang H-W, Lu M-H, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 2010;70(8):3119-27.
31. Banno K, Iida M, Yanokura M, et al. MicroRNA in cervical cancer: OncomiRs and tumor suppressor miRs in diagnosis and treatment. ScientificWorldJournal. 2014;2014(1):178075.
32. Zhang C-M, Zhao J, Deng H-Y. MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1. J Biomed Sci. 2013;20(1):79.
33. Marsolier J, Pineau S, Medjkane S, et al. OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes. PLoS Pathog. 2013;9(4):e1003222.
34. Zhang C-M, Zhao J, Deng H-Y. MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1. J Biomed Sci. 2013;20(1):1-10.
35. Tang B, Xiao B, Liu Z, et al. Identification of MyD88 as a novel target of miR-155, involved in negative regulation of Helicobacter pylori-induced inflammation. FEBS Lett. 2010;584(8):1481-6.
36. Zheng X, Huang H, Liu J, Li M, Liu M, Luo T. Propofol attenuates inflammatory response in LPS-activated microglia by regulating the miR-155/SOCS1 pathway. Inflammation. 2018;41(1):11-9.
37. Jablonski KA, Gaudet AD, Amici SA, Popovich PG, Guerau-de-Arellano M. Control of the inflammatory macrophage transcriptional signature by miR-155. PLoS One. 2016;11(7):e0159724.
38. Sun Y, Wang M, Lin G, et al. Serum microRNA-155 as a potential biomarker to track disease in breast cancer. 2012.
39. Chernyy V, Pustylnyak V, Kozlov V, Gulyaeva L. Increased expression of miR-155 and miR-222 is associated with lymph node positive status. J Cancer. 2018;9(1):135.
40. Petrović N, Kolaković A, Stanković A, et al. miR-155 expression level changes might be associated with initial phases of breast cancer pathogenesis and lymph-node metastasis. Cancer Biomark. 2016;16(3):385-94.
41. Zare A, Alipoor B, Omrani MD, Zali MR, Alamdari NM, Ghaedi H. Decreased miR-155-5p, miR-15a, and miR-186 expression in gastric cancer is associated with advanced tumor grade and metastasis. Iran Biomed J. 2019;23(5):338.
42. Chen X, Oppenheim JJ. Resolving the identity myth: key markers of functional CD4+ FoxP3+ regulatory T cells. Int Immunopharmacol. 2011;11(10):1489-96.
43. Li C, Jiang P, Wei S, Xu X, Wang J. Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol Cancer. 2020;19(1):1-23.
44. Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, Okada M. Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother. 2009;58(3):441-7.
45. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373-80.
46. Liu W, Ouyang H, Zeng Q, Luo R, Lu G. Decreased Treg-derived miR-181a and miR-155 correlated with reduced number and function of Treg cells in allergic rhinitis children. Eur Arch Otorhinolaryngol. 2019;276(4):1089-94.
47. Blüml S, Bonelli M, Niederreiter B, et al. Essential role of microRNA‐155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum. 2011;63(5):1281-8.
48. Gao S, Wang Y, Wang M, et al. MicroRNA-155, induced by FOXP3 through transcriptional repression of BRCA1, is associated with tumor initiation in human breast cancer. Oncotarget. 2017;8(25):41451.
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| Breast cancer MicroRNA-155 Peripheral blood mononuclear cell Regulatory T cell | ||
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How to Cite
1.
Iranparast S, Tahmasebi-Birgani M, Motamedfar A, Amari A, Ghafourian M. Coordinated Rise of miR-155-5p and Regulatory T Cells in Peripheral Blood Mononuclear Cells: An Early Event in Newly Diagnosed Breast Cancer Pathogenesis. Iran J Allergy Asthma Immunol. 2026;:1-9.
