Tumor Biology

, Volume 37, Issue 8, pp 10011–10019 | Cite as

Crosstalk between TGF-β signaling and miRNAs in breast cancer metastasis

  • Wei Chen
  • Siying Zhou
  • Ling Mao
  • Heda Zhang
  • Dawei Sun
  • Junying Zhang
  • JIan Li
  • Jin-hai Tang


Transforming growth factor-β (TGF-β) signaling pathway is a key regulator of various cancer biologies, including cancer cell migration, invasion, angiogenesis, proliferation, as well as apoptosis, and it is one of indispensable signaling pathways during cancer metastasis. TGF-β signaling pathway can regulate and be regulated by a series of molecular and signaling pathways where microRNAs (miRNAs) seem to play important roles. miRNAs are small non-coding RNAs that can regulate expressions of their target genes. Emerging evidence suggest that miRNAs participate in various biological and pathologic processes such as cancer cells apoptosis, proliferation, invasion, migration, and metastasis by influencing multiple signaling pathways. In this article, we focus on the interaction between miRNAs and TGF-β in breast cancer (BC) metastasis through modulating invasion-metastasis-related factors, including epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), matrix metalloproteinase (MMP), tissue inhibitors of MMPs (TIMPs), cell adhesion molecules (CAMs), and tumor microenvironment (TME). Through a clear understanding of the complicated links between TGF-β pathway and miRNAs, it may provide a novel and safer therapeutic target to prevent BC metastasis.


TGF-β pathway miRNAs Breast cancer Metastasis Therapy 



This work was supported by grants from the National Natural Science Foundation of China (81272470).

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Papadimitriou E, Vasilaki E, Vorvis C, Iliopoulos D, Moustakas A, Kardassis D, et al. Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-beta and miR-24: role in epithelial-to-mesenchymal transition. Oncogene. 2012;31:2862–75.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhao B, Chen Y-G. Regulation of TGF-β signal transduction. Scientifica (Cairo). 2014;2014:874065.Google Scholar
  3. 3.
    Derynck R, Zhang YE. SMAD-dependent and SMAD-independent pathways in TGF-beta family signalling. Nature. 2003;425:577–84.CrossRefPubMedGoogle Scholar
  4. 4.
    Mu Y, Gudey SK, Landström M. Non-SMAD signaling pathways. Cell Tissue Res. 2012;347(1):11–20.CrossRefPubMedGoogle Scholar
  5. 5.
    Akhurst RJ, Padgett RW. Matters of context guide future research in TG-β superfamily signaling. Sci Signal. 2015;8(399):re10.CrossRefPubMedGoogle Scholar
  6. 6.
    Dumont N, Arteaga CL. Targeting the TGF-beta signaling network in human neoplasia. Cancer Cell. 2003;3:531–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Roberts AB, Wakefield LM. The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci U S A. 2003;100:8621–3.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tang J, Li L, Huang W, Sui C, Yang Y, Lin X, et al. miR-429 increases the metastatic capability of HCC via regulating classic Wnt pathway rather than epithelial-mesenchymal transition. Cancer Lett. 2015;364:33–43.CrossRefPubMedGoogle Scholar
  9. 9.
    Hu J, Xu J, Wu Y, Chen Q, Zheng W, Lu X, et al. Identification of microRNA-93 as a functional dysregulated miRNA in triple-negative breast cancer. Tumour Biol. 2015;36:251–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Ma C, Nong K, Zhu H, Wang W, Huang X, Yuan Z, et al. H19 promotes pancreatic cancer metastasis by derepressing let-7’s suppression on its target HMGA2-mediated EMT. Tumour Biol. 2014;35(9):9163–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Deng S, Zhu S, Wang B, Li X, Liu Y, Qin Q, et al. Chronic pancreatitis and pancreatic cancer demonstrate active epithelial-mesenchymal transition profile, regulated by miR-217-SIRT1 pathway. Cancer Lett. 2014;355:184–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Xie H, Li L, Zhu G, Dang Q, Ma Z, He D, et al. Infiltrated pre-adipocytes increase prostate cancer metastasis via modulation of the miR-301a/androgen receptor (AR)/TGF-beta1/SMAD/MMP9 signals. Oncotarget. 2015;6:12326–39.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Soria-Valles C, Gutierrez-Fernandez A, Guiu M, Mari B, Fueyo A, Gomis RR, et al. The anti-metastatic activity of collagenase-2 in breast cancer cells is mediated by a signaling pathway involving decorin and miR-21. Oncogene. 2014;33:3054–63.CrossRefPubMedGoogle Scholar
  14. 14.
    Hurst DR, Welch DR. Metastasis suppressor genes at the interface between the environment and tumor cell growth. Int Rev Cell Mol Biol. 2011;286:107–80.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Rozenchan PB, Pasini FS, Roela RA, Katayama ML, Mundim FG, Brentani H, et al. Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer. Tumour Biol. 2015. DOI: 10.1007/s13277-015-3727-1.
  16. 16.
    Welch DR, Hurst DR. Unraveling the ‘TGF-β paradox’ one metastamir at a time. Breast Cancer Res. 2013;15:305.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Berx G, Raspe E, Christofori G, Thiery JP, Sleeman JP. Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin Exp Metastasis. 2007;24:587–97.CrossRefPubMedGoogle Scholar
  18. 18.
    Morrison CD, Parvani JG, Schiemann WP. The relevance of the TGF-beta paradox to EMT-MET programs. Cancer Lett. 2013;341:30–40.CrossRefPubMedGoogle Scholar
  19. 19.
    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.CrossRefPubMedGoogle Scholar
  20. 20.
    Jiang HL, Sun HF, Gao SP, Li LD, Hu X, Wu J, et al. Loss of RAB1B promotes triple-negative breast cancer metastasis by activating TGF-β/SMAD signaling. Oncotarget. 2015;6:16352–65.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, et al. An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial- mesenchymal transition. Mol Biol Cell. 2011;22:1686–98.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pecot CV, Rupaimoole R, Yang D, Akbani R, Ivan C, Lu C, et al. Tumour angiogenesis regulation by the miR-200 family. Nat Commun. 2013;4:2427.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008;9:582–9.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Perdigão-Henriques R, Petrocca F, Altschuler G, Thomas MP, Le MT, Tan SM, et al. miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the ZEB2 and SNAIL1 transcriptional repressor complexes. Oncogene. 2015. doi:  10.1038/onc.2015.69.
  25. 25.
    Peng J, Yoshioka Y, Mandai M, Matsumura N, Baba T, Yamaguchi K, et al. The BMP signaling pathway leads to enhanced proliferation in serous ovarian cancer—a potential therapeutic target. Mol Carcinog. 2015. doi:  10.1002/mc.22283.
  26. 26.
    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;286:25992–6002.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang J, Tian XJ, Zhang H, Teng Y, Li R, Bai F, et al. TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci Signal. 2014;7(345):ra91.CrossRefPubMedGoogle Scholar
  29. 29.
    Turcatel G, Rubin N, El-Hashash A, Warburton D. miR-99a and miR-99b modulate TGF-beta induced epithelial to mesenchymal plasticity in normal murine mammary gland cells. PLoS One. 2012;7:e31032.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Johansson J, Berg T, Kurzejamska E, Pang MF, Tabor V, Jansson M, et al. miR-155-mediated loss of C/EBPβ shifts the TGF-β response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer. Oncogene. 2013;32:5614–24.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, et al. MicroRNA-155 is regulated by the transforming growth factor beta/SMAD pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol. 2008;28:6773–84.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hong S, Noh H, Teng Y, Shao J, Rehmani H, Ding HF, et al. SHOX2 is a direct miR-375 target and a novel epithelial-to-mesenchymal transition inducer in breast cancer cells. Neoplasia. 2014;16:279–90.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ding X, Park SI, McCauley LK, Wang CY. Signaling between transforming growth factor β (TGF-β) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial-mesenchymal transition and tumor metastasis. J Biol Chem. 2013;288:10241–53.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Smith AL, Iwanaga R, Drasin DJ, Micalizzi DS, Vartuli RL, Tan AC, et al. The miR-106b-25 cluster targets SMAD7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene. 2012;31:5162–71.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D, Schiemann WP. TGF-β upregulates miR-181a expression to promote breast cancer metastasis. J Clin Invest. 2013;123:150–63.CrossRefPubMedGoogle Scholar
  36. 36.
    Han X, Yan S, Weijie Z, Feng W, Liuxing W, Mengquan L, et al. Critical role of miR-10b in transforming growth factor-β1-induced epithelial-mesenchymal transition in breast cancer. Cancer Gene Ther. 2014;21:60–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Chuthapisith S, Eremin J, El-Sheemey M, Eremin O. Breast cancer chemoresistance: emerging importance of cancer stem cells. Surg Oncol. 2010;19:27–32.CrossRefPubMedGoogle Scholar
  38. 38.
    Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports. 2013;2:78–91.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wang Y, Yu Y, Tsuyada A, Ren X, Wu X, Stubblefield K, et al. Transforming growth factor-β regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene. 2011;30:1470–80.CrossRefPubMedGoogle Scholar
  40. 40.
    Qian P, Banerjee A, Wu ZS, Zhang X, Wang H, Pandey V, et al. Loss of SNAIL regulated miR-128-2 on chromosome 3p22.3 targets multiple stem cell factors to promote transformation of mammary epithelial cells. Cancer Res. 2012;72:6036–50.CrossRefPubMedGoogle Scholar
  41. 41.
    Christofori G. Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. EMBO J. 2003;22:2318–23.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lin CW, Liao MY, Lin WW, Wang YP, Lu TY, Wu HC. Epithelial cell adhesion molecule regulates tumor initiation and tumorigenesis via activating reprogramming factors and epithelial-mesenchymal transition gene expression in colon cancer. J Biol Chem. 2012;287:39449–59.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68:3645–54.CrossRefPubMedGoogle Scholar
  44. 44.
    Truong HH, Xiong J, Ghotra VP, Nirmala E, Haazen L, Le Dévédec SE, et al. β1 integrin inhibition elicits a prometastatic switch through the TGFβ-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer. Sci Signal. 2014;7:ra15.CrossRefPubMedGoogle Scholar
  45. 45.
    Ampuja M, Jokimäki R, Juuti-Uusitalo K, Rodriguez-Martinez A, Alarmo EL, Kallioniemi A. BMP4 inhibits the proliferation of breast cancer cells and induces an MMP-dependent migratory phenotype in MDA-MB-231 cells in 3D environment. BMC Cancer. 2013;13:42.CrossRefGoogle Scholar
  46. 46.
    Wang B, Hsu SH, Majumder S, Kutay H, Huang W, Jacob ST, et al. TGF-beta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene. 2010;29:1787–97.CrossRefPubMedGoogle Scholar
  47. 47.
    Liu Y, Lai L, Chen Q, Song Y, Xu S, Ma F, et al. MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. J Immunol. 2012;188:5500–10.CrossRefPubMedGoogle Scholar
  48. 48.
    Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest. 2011;121:3804–9.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Jang JY, Lee JK, Jeon YK, Kim CW. Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization. BMC Cancer. 2013;13:421.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Xu Q, Wang L, Li H, Han Q, Li J, Qu X, et al. Mesenchymal stem cells play a potential role in regulating the establishment and maintenance of epithelial-mesenchymal transition in MCF7 human breast cancer cells by paracrine and induced autocrine TGF-β. Int J Oncol. 2012;41:959–68.PubMedGoogle Scholar
  51. 51.
    Nagpal N, Ahmad HM, Chameettachal S, Sundar D, Ghosh S, Kulshreshtha R. HIF-inducible miR-191 promotes migration in breast cancer through complex regulation of TGFβ-signaling in hypoxic microenvironment. Sci Rep. 2015;5:9650.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Pollari S, Leivonen SK, Perälä M, Fey V, Käkönen SM, Kallioniemi O. Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells. PLoS One. 2012;7:e37361.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wang SE. The functional crosstalk between HER2 tyrosine kinase and TGF-beta signaling in breast cancer malignancy. J Signal Transduct. 2011;2011:804236.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Moustakas A, Heldin CH. Non-SMAD TGF-beta signals. J Cell Sci. 2005;118:3573–84.CrossRefPubMedGoogle Scholar
  55. 55.
    Javelaud D, Mauviel A. Crosstalk mechanisms between the mitogen-activated protein kinase pathways and SMAD signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene. 2005;24:5742–50.CrossRefPubMedGoogle Scholar
  56. 56.
    Akalay I, Tan TZ, Kumar P, Janji B, Mami-Chouaib F, Charpy C, et al. Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene. 2015;34:2261–71.CrossRefPubMedGoogle Scholar
  57. 57.
    Keklikoglou I, Koerner C, Schmidt C, Zhang JD, Heckmann D, Shavinskaya A, et al. MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways. Oncogene. 2012;31:4150–63.CrossRefPubMedGoogle Scholar
  58. 58.
    Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, et al. MicroRNAs differentially regulated by AKT isoforms control EMT and stem cell renewal in cancer cells. Sci Signal. 2009;2:ra62.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Wei Z, Cui L, Mei Z, Liu M, Zhang D. miR-181a mediates metabolic shift in colon cancer cells via the PTEN/AKT pathway. FEBS Lett. 2014;588(9):1773–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Zheng J, Wu C, Xu Z, Xia P, Dong P, Chen B, et al. Hepatic stellate cell is activated by microRNA-181b via PTEN/AKT pathway. Mol Cell Biochem. 2015;398(1-2):1–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Mele F, Basso C, Leoni C, Aschenbrenner D, Becattini S, Latorre D, et al. ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells. Nat Commun. 2015;6:6431.CrossRefPubMedGoogle Scholar
  62. 62.
    Brunen D, Willems SM, Kellner U, Midgley R, Simon I, Bernards R. TGF-β: an emerging player in drug resistance. Cell Cycle. 2013;12:2960–8.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Bai WD, Ye XM, Zhang MY, Zhu HY, Xi WJ, Huang X, et al. miR-200c suppresses TGF-β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer. Int J Cancer. 2014;135:1356–68.CrossRefPubMedGoogle Scholar
  64. 64.
    Rao X, Di Leva G, Li M, Fang F, Devlin C, Hartman-Frey C, et al. MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. Oncogene. 2011;30:1082–97.CrossRefPubMedGoogle Scholar
  65. 65.
    Jiang F, Li Y, Mu J, Hu C, Zhou M, Wang X, et al. Glabridin inhibits cancer stem cell-like properties of human breast cancer cells: an epigenetic regulation of miR-148a/SMAD2 signaling. Mol Carcinog. 2015. doi:  10.1002/mc.22333.
  66. 66.
    Yu Y, Wang Y, Ren X, Tsuyada A, Li A, Liu LJ, et al. Context-dependent bidirectional regulation of the MutS homolog 2 by transforming growth factor β contributes to chemoresistance in breast cancer cells. Mol Cancer Res. 2010;8:1633–42.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Zhong S, Ma T, Zhang X, Lv M, Chen L, Tang JH, et al. MicroRNA expression profiling and bioinformatics analysis of dysregulated microRNAs in vinorelbine-resistant breast cancer cells. Gene. 2015;556:113–8.CrossRefPubMedGoogle Scholar
  68. 68.
    Lv J, Ziyi F, Shi M, Xia K, Ji C, Xu P, et al. Systematic analysis of gene expression pattern in has-miR-760 overexpressed resistance of the MCF-7 human breast cancer cell to doxorubicin. Biomed Pharmacother. 2015;69:162–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Wei Chen
    • 1
  • Siying Zhou
    • 2
    • 3
  • Ling Mao
    • 4
  • Heda Zhang
    • 1
    • 2
  • Dawei Sun
    • 5
  • Junying Zhang
    • 5
  • JIan Li
    • 2
  • Jin-hai Tang
    • 1
    • 5
  1. 1.Xuzhou Medical CollegeXuzhouChina
  2. 2.Department of General SurgeryJiangsu Cancer Hospital Affiliated to Nanjing Medical UniversityNanjingChina
  3. 3.The First Clinical Medical CollegeNanjing University of Chinese MedicineNanjingChina
  4. 4.Department of General SurgeryHuaian Second People’s HospitalHuaianChina
  5. 5.Jiangsu Cancer Hospital Affiliated to Nanjing Medical UniversityCancer Institute of Jiangsu ProvinceNanjingChina

Personalised recommendations