Skip to main content

Advertisement

SpringerLink
Log in

Epithelial-to-Mesenchymal Transition Signaling Pathways Responsible for Breast Cancer Metastasis

  • Review
  • Published:
Cellular and Molecular Bioengineering Aims and scope Submit manuscript

Abstract

Breast carcinoma is highly metastatic and invasive. Tumor metastasis is a convoluted and multistep process involving tumor cell disseminating from their primary site and migrating to the secondary organ. Epithelial-mesenchymal transition (EMT) is one of the crucial steps that initiate cell progression, invasion, and metastasis. During EMT, epithelial cells alter their molecular features and acquire a mesenchymal phenotype. The regulation of EMT is centered by several signaling pathways, including primary mediators TGF-β, Notch, Wnt, TNF-α, Hedgehog, and RTKs. It is also affected by hypoxia and microRNAs (miRNAs). All these pathways are the convergence on the transcriptional factors such as Snail, Slug, Twist, and ZEB1/2. In addition, a line of evidence suggested that EMT and cancer stem like cells (CSCs) are associated. EMT associated cancer stem cells display mesenchymal phenotypes and resist to chemotherapy or targeted therapy. In this review, we highlighted recent discoveries in these signaling pathways and their regulation in breast cancer metastasis and invasion. While the clinical relevance of EMT and breast cancers remains controversial, we speculated a convergent signaling network pivotal to elucidating the transition of epithelial to mesenchymal phenotypes and onset of metastasis of breast cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

Abbreviations

AJ:

Adherent junctions

AS:

Alternative splicing

CSCs:

Cancer stem cells

CT:

Chemotherapy

EMT:

Epithelial Mesenchymal Cell Transition

ER:

Estrogen receptor

HER-2:

Human epidermal growth factor receptor 2

miRNA:

MicroRNA

PR:

Progesterone receptor

TJ:

Tight junctions

TGF:

Transforming growth factor

TNBC:

Triple-negative breast cancer

TNF:

Tumor necrosis factor

References

  1. Acloque, H., M. S. Adams, K. Fishwick, M. Bronner-Fraser, and M. A. Nieto. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J. Clin. Invest. 119:1438–1449, 2009.

    Google Scholar 

  2. Ai, M., K. Liang, Y. Lu, S. Qiu, and Z. Fan. Brk/PTK6 cooperates with HER2 and Src in regulating breast cancer cell survival and epithelial-to-mesenchymal transition. Cancer Biol. Ther. 14:237–245, 2013.

    Google Scholar 

  3. Aiello, N. M., and Y. Kang. Context-dependent EMT programs in cancer metastasis. J. Exp. Med. 216:1016–1026, 2019.

    Google Scholar 

  4. Armas-Lopez, L., J. Zuniga, O. Arrieta, and F. Avila-Moreno. The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy. Oncotarget. 8:60684–60703, 2017.

    Google Scholar 

  5. Barriere, G., P. Fici, G. Gallerani, F. Fabbri, and M. Rigaud. Epithelial mesenchymal transition: a double-edged sword. Clin. Transl. Med. 4:14, 2015.

    Google Scholar 

  6. Battula, V. L., et al. Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells. 28:1435–1445, 2010.

    Google Scholar 

  7. Beurel, E., S. F. Grieco, and R. S. Jope. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol. Ther. 148:114–131, 2015.

    Google Scholar 

  8. Bhateja, P., Cherian, M., Majumder, S. & Ramaswamy, B. The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer? Cancers (Basel) 11 (2019).

  9. Brabletz, S., and T. Brabletz. The ZEB/miR-200 feedback loop–a motor of cellular plasticity in development and cancer? EMBO Rep. 11:670–677, 2010.

    Google Scholar 

  10. Carpenter, R. L., I. Paw, M. W. Dewhirst, and H. W. Lo. Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells. Oncogene. 34:546–557, 2015.

    Google Scholar 

  11. Chen, T., Y. You, H. Jiang, and Z. Z. Wang. Epithelial-mesenchymal transition (EMT): a biological process in the development, stem cell differentiation, and tumorigenesis. J. Cell Physiol. 232:3261–3272, 2017.

    Google Scholar 

  12. Chiang, C., and K. Ayyanathan. Snail/Gfi-1 (SNAG) family zinc finger proteins in transcription regulation, chromatin dynamics, cell signaling, development, and disease. Cytokine Growth Factor Rev. 24:123–131, 2013.

    Google Scholar 

  13. Chiang, S. P., R. M. Cabrera, and J. E. Segall. Tumor cell intravasation. Am. J. Physiol. Cell Physiol. 311:C1–C14, 2016.

    Google Scholar 

  14. Chou, C. C., et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 74:4783–4795, 2014.

    Google Scholar 

  15. Colavito, S. A., M. R. Zou, Q. Yan, D. X. Nguyen, and D. F. Stern. Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) pathway. Breast Cancer Res. 16:444, 2014.

    Google Scholar 

  16. Creighton, C. J., et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl. Acad. Sci. U.S.A. 106:13820–13825, 2009.

    Google Scholar 

  17. Dai, X., et al. Breast cancer intrinsic subtype classification, clinical use and future trends. Am. J. Cancer Res. 5:2929–2943, 2015.

    Google Scholar 

  18. Dias, K., et al. Claudin-low breast cancer; clinical & pathological characteristics. PLoS ONE. 12:e0168669, 2017.

    Google Scholar 

  19. Diaz, V. M., R. Vinas-Castells, and A. Garcia de Herreros. Regulation of the protein stability of EMT transcription factors. Cell. Adh Migr. 8:418–428, 2014.

    Google Scholar 

  20. Do, H. T. T., and J. Cho. Involvement of the ERK/HIF-1alpha/EMT pathway in XCL1-induced migration of MDA-MB-231 and SK-BR-3 breast cancer cells. Int. J. Mol. Sci. 22:89, 2020.

    Google Scholar 

  21. Eliyatkin, N., E. Yalcin, B. Zengel, S. Aktas, and E. Vardar. Molecular classification of breast carcinoma: from traditional, old-fashioned way to a new age, and a new way. J. Breast Health. 11:59–66, 2015.

    Google Scholar 

  22. English, D. P., D. M. Roque, and A. D. Santin. HER2 expression beyond breast cancer: therapeutic implications for gynecologic malignancies. Mol. Diagn. Ther. 17:85–99, 2013.

    Google Scholar 

  23. Fares, J., M. Y. Fares, H. H. Khachfe, H. A. Salhab, and Y. Fares. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct. Target Ther. 5:28, 2020.

    Google Scholar 

  24. Farnie, G., and R. B. Clarke. Mammary stem cells and breast cancer–role of Notch signalling. Stem Cell Rev. 3:169–175, 2007.

    Google Scholar 

  25. Fedele, M., L. Cerchia, and G. Chiappetta. The epithelial-to-mesenchymal transition in breast cancer: focus on basal-like carcinomas. Cancers (Basel). 9:134, 2017.

    Google Scholar 

  26. Feng, Y., et al. Breast cancer development and progression: risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis. 5:77–106, 2018.

    Google Scholar 

  27. Feng, X., Z. Wang, R. Fillmore, and Y. Xi. MiR-200, a new star miRNA in human cancer. Cancer Lett. 344:166–173, 2014.

    Google Scholar 

  28. Fragomeni, S. M., A. Sciallis, and J. S. Jeruss. Molecular subtypes and local-regional control of breast cancer. Surg. Oncol. Clin. N.Am. 27:95–120, 2018.

    Google Scholar 

  29. De Francesco, E. M., M. Maggiolini, and A. M. Musti. Crosstalk between Notch, HIF-1alpha and GPER in breast cancer EMT. Int. J. Mol. Sci. 19:2011, 2018.

    Google Scholar 

  30. Friedl, P., and S. Alexander. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 147:992–1009, 2011.

    Google Scholar 

  31. Garg, M. Epithelial-mesenchymal transition - activating transcription factors - multifunctional regulators in cancer. World J. Stem Cells. 5:188–195, 2013.

    Google Scholar 

  32. Georgakopoulos-Soares, I., D. V. Chartoumpekis, V. Kyriazopoulou, and A. Zaravinos. EMT factors and metabolic pathways in cancer. Front. Oncol. 10:499, 2020.

    Google Scholar 

  33. Geyer, F. C., et al. beta-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod. Pathol. 24:209–231, 2011.

    Google Scholar 

  34. Ghildiyal, M., and P. D. Zamore. Small silencing RNAs: an expanding universe. Nat. Rev. Genet. 10:94–108, 2009.

    Google Scholar 

  35. Gilkes, D. M., and G. L. Semenza. Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol. 9:1623–1636, 2013.

    Google Scholar 

  36. Giuli, M. V., E. Giuliani, I. Screpanti, D. Bellavia, and S. Checquolo. Notch Signaling Activation as a Hallmark for Triple-Negative Breast Cancer Subtype. J Oncol. 2019:8707053, 2019.

    Google Scholar 

  37. Goncalves, V., J. F. S. Pereira, and P. Jordan. Signaling pathways driving aberrant splicing in cancer cells. Genes (Basel). 9:9, 2017.

    Google Scholar 

  38. Gonzalez, D. M., and D. Medici. Signaling mechanisms of the epithelial-mesenchymal transition. Sci. Signal. 7:re8, 2014.

    Google Scholar 

  39. Hao, Y., D. Baker, and P. Ten Dijke. TGF-beta-Mediated epithelial-mesenchymal transition and cancer metastasis. Int. J. Mol. Sci. 20:2767, 2019.

    Google Scholar 

  40. Hassan, B., A. Akcakanat, A. M. Holder, and F. Meric-Bernstam. Targeting the PI3-kinase/Akt/mTOR signaling pathway. Surg. Oncol. Clin. N. Am. 22:641–664, 2013.

    Google Scholar 

  41. Hata, A., and Y. G. Chen. TGF-beta Signaling from receptors to Smads. Cold Spring Harb. Perspect. Biol. 8:a022061, 2016.

    Google Scholar 

  42. Hollier, B. G., K. Evans, and S. A. Mani. The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol. Neoplasia. 14:29–43, 2009.

    Google Scholar 

  43. Hong, J., et al. Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. 71:3980–3990, 2011.

    Google Scholar 

  44. Horiuchi, T., H. Mitoma, S. Harashima, H. Tsukamoto, and T. Shimoda. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford). 49:1215–1228, 2010.

    Google Scholar 

  45. Hua, W., P. Ten Dijke, S. Kostidis, M. Giera, and M. Hornsveld. TGFbeta-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer. Cell Mol. Life Sci. 77:2103–2123, 2020.

    Google Scholar 

  46. Hubalek, M., T. Czech, and H. Muller. Biological subtypes of triple-negative breast cancer. Breast Care (Basel). 12:8–14, 2017.

    Google Scholar 

  47. Ishida, T., H. Hijioka, K. Kume, A. Miyawaki, and N. Nakamura. Notch signaling induces EMT in OSCC cell lines in a hypoxic environment. Oncol. Lett. 6:1201–1206, 2013.

    Google Scholar 

  48. Jeng, K. S., I. S. Sheen, C. M. Leu, P. H. Tseng, and C. F. Chang. The role of smoothened in cancer. Int. J. Mol. Sci. 21:6863, 2020.

    Google Scholar 

  49. Ji, J., and X. W. Wang. Clinical implications of cancer stem cell biology in hepatocellular carcinoma. Semin. Oncol. 39:461–472, 2012.

    Google Scholar 

  50. Jiang, W., J. Peng, Y. Zhang, W. C. Cho, and K. Jin. The implications of cancer stem cells for cancer therapy. Int. J. Mol. Sci. 13:16636–16657, 2012.

    Google Scholar 

  51. Jogi, A., A. Ehinger, L. Hartman, and S. Alkner. Expression of HIF-1alpha is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer. PLoS ONE. 14:e0226150, 2019.

    Google Scholar 

  52. Kalluri, R., and R. A. Weinberg. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119:1420–1428, 2009.

    Google Scholar 

  53. Kasper, M., V. Jaks, M. Fiaschi, and R. Toftgard. Hedgehog signalling in breast cancer. Carcinogenesis. 30:903–911, 2009.

    Google Scholar 

  54. Katz, E., et al. An in vitro model that recapitulates the epithelial to mesenchymal transition (EMT) in human breast cancer. PLoS ONE. 6:e17083, 2011.

    Google Scholar 

  55. Kim, D. H., et al. Epithelial mesenchymal transition in embryonic development, tissue repair and cancer: a comprehensive overview. J. Clin. Med. 7:1, 2017.

    Google Scholar 

  56. Komiya, Y., and R. Habas. Wnt signal transduction pathways. Organogenesis. 4:68–75, 2008.

    Google Scholar 

  57. Kontomanolis, E. N., et al. The notch pathway in breast cancer progression. Sci. World J. 2018. https://doi.org/10.1155/2018/2415489.

    Article  Google Scholar 

  58. Lacroix-Triki, M., et al. beta-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast. Mod. Pathol. 23:1438–1448, 2010.

    Google Scholar 

  59. Lambert, A. W., D. R. Pattabiraman, and R. A. Weinberg. Emerging biological principles of metastasis. Cell. 168:670–691, 2017.

    Google Scholar 

  60. Lamouille, S., J. Xu, and R. Derynck. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15:178–196, 2014.

    Google Scholar 

  61. Lee, S. Y., et al. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol. Cancer. 16:10, 2017.

    Google Scholar 

  62. Lemmon, M. A., and J. Schlessinger. Cell signaling by receptor tyrosine kinases. Cell. 141:1117–1134, 2010.

    Google Scholar 

  63. Leone, K., C. Poggiana, and R. Zamarchi. The interplay between circulating tumor cells and the immune system: from immune escape to cancer immunotherapy. Diagnostics (Basel). 8:59, 2018.

    Google Scholar 

  64. Li, C. W., et al. Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res. 72:1290–1300, 2012.

    Google Scholar 

  65. Li, Y., et al. Regulation of EMT by Notch signaling pathway in tumor progression. Curr. Cancer Drug Targets. 13:957–962, 2013.

    Google Scholar 

  66. Li, J., and B. P. Zhou. Activation of beta-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer. 11:49, 2011.

    Google Scholar 

  67. Liao, W. T., Y. P. Ye, Y. J. Deng, X. W. Bian, and Y. Q. Ding. Metastatic cancer stem cells: from the concept to therapeutics. Am. J. Stem Cells. 3:46–62, 2014.

    Google Scholar 

  68. Lindsey, S., and S. A. Langhans. Epidermal growth factor signaling in transformed cells. Int. Rev. Cell Mol. Biol. 314:1–41, 2015.

    Google Scholar 

  69. MacDonald, B. T., K. Tamai, and X. He. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell. 17:9–26, 2009.

    Google Scholar 

  70. Mani, S. A., et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715, 2008.

    Google Scholar 

  71. Martin, T. A., A. Goyal, G. Watkins, and W. G. Jiang. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann. Surg. Oncol. 12:488–496, 2005.

    Google Scholar 

  72. Mercogliano, M. F., S. Bruni, P. V. Elizalde, and R. Schillaci. Tumor necrosis factor alpha blockade: an opportunity to tackle breast cancer. Front. Oncol. 10:584, 2020.

    Google Scholar 

  73. Mezencev, R., L. V. Matyunina, N. Jabbari, and J. F. McDonald. Snail-induced epithelial-to-mesenchymal transition of MCF-7 breast cancer cells: systems analysis of molecular changes and their effect on radiation and drug sensitivity. BMC Cancer. 16:236, 2016.

    Google Scholar 

  74. Mezi, S., et al. Standard of care and promising new agents for the treatment of mesenchymal triple-negative breast cancer. Cancers (Basel). 13:1080, 2021.

    Google Scholar 

  75. Moyret-Lalle, C., E. Ruiz, and A. Puisieux. Epithelial-mesenchymal transition transcription factors and miRNAs: “Plastic surgeons” of breast cancer. World J. Clin. Oncol. 5:311–322, 2014.

    Google Scholar 

  76. Mukherjee, N., et al. Subtype-specific alterations of the Wnt signaling pathway in breast cancer: clinical and prognostic significance. Cancer Sci. 103:210–220, 2012.

    Google Scholar 

  77. Muz, B., P. de la Puente, F. Azab, and A. K. Azab. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl). 3:83–92, 2015.

    Google Scholar 

  78. Nami, B., and Z. Wang. HER2 in breast cancer stemness: a negative feedback loop towards Trastuzumab resistance. Cancers (Basel). 9:40, 2017.

    Google Scholar 

  79. Nieto, M. A. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu. Rev. Cell Dev. Biol. 27:347–376, 2011.

    Google Scholar 

  80. Niewiadomski, P., et al. Gli proteins: regulation in development and cancer. Cells. 8:147, 2019.

    Google Scholar 

  81. Nourmohammadi, B., et al. Expression of miR-9 and miR-200c, ZEB1, ZEB2 and E-cadherin in non-small cell lung cancers in Iran. Asian Pac. J. Cancer Prev. 20:1633–1639, 2019.

    Google Scholar 

  82. Okita, Y. et al. The transcription factor MAFK induces EMT and malignant progression of triple-negative breast cancer cells through its target GPNMB. Sci Signal 10 (2017).

  83. Olea-Flores, M., et al. Extracellular-signal regulated kinase: a central molecule driving epithelial-mesenchymal transition in cancer. Int. J. Mol. Sci. 20:2885, 2019.

    Google Scholar 

  84. Owen, K. L., N. K. Brockwell, and B. S. Parker. JAK-STAT signaling: a double-edged sword of immune regulation and cancer progression. Cancers (Basel). 11:2002, 2019.

    Google Scholar 

  85. Patel, M., S. Nowsheen, S. Maraboyina, and F. Xia. The role of poly(ADP-ribose) polymerase inhibitors in the treatment of cancer and methods to overcome resistance: a review. Cell Biosci. 10:35, 2020.

    Google Scholar 

  86. Peinado, H., E. Ballestar, M. Esteller, and A. Cano. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol. Cell Biol. 24:306–319, 2004.

    Google Scholar 

  87. Pelullo, M., et al. Wnt, Notch, and TGF-beta pathways impinge on hedgehog signaling complexity: an open window on cancer. Front. Genet. 10:711, 2019.

    Google Scholar 

  88. Pernas, S., and S. M. Tolaney. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther. Adv. Med. Oncol. 11:1758835919833519, 2019.

    Google Scholar 

  89. Piasecka, D., M. Braun, R. Kordek, R. Sadej, and H. Romanska. MicroRNAs in regulation of triple-negative breast cancer progression. J. Cancer Res. Clin. Oncol. 144:1401–1411, 2018.

    Google Scholar 

  90. Pohl, S. G., et al. Wnt signaling in triple-negative breast cancer. Oncogenesis. 6:e310, 2017.

    Google Scholar 

  91. Polyak, K., and R. A. Weinberg. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer. 9:265–273, 2009.

    Google Scholar 

  92. Prat, A., et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12:R68, 2010.

    Google Scholar 

  93. Puisieux, A., S. Valsesia-Wittmann, and S. Ansieau. A twist for survival and cancer progression. Br. J. Cancer. 94:13–17, 2006.

    Google Scholar 

  94. Radisky, D. C., and M. A. LaBarge. Epithelial-mesenchymal transition and the stem cell phenotype. Cell Stem Cell. 2:511–512, 2008.

    Google Scholar 

  95. Rajc, J., I. Frohlich, M. Mrcela, I. Tomas, and J. Flam. Prognostic impact of low estrogen and progesterone positivity in luminal B (Her2 Negative) breast cancer. Acta Clin. Croat. 57:425–433, 2018.

    Google Scholar 

  96. Rajput, S., Z. Guo, S. Li, and C. X. Ma. PI3K inhibition enhances the anti-tumor effect of eribulin in triple negative breast cancer. Oncotarget. 10:3667–3680, 2019.

    Google Scholar 

  97. Rampurwala, M., K. B. Wisinski, and R. O’Regan. Role of the androgen receptor in triple-negative breast cancer. Clin Adv Hematol Oncol. 14:186–193, 2016.

    Google Scholar 

  98. Ren, Q., J. Chen, and Y. Liu. LRP5 and LRP6 in wnt signaling: similarity and divergence. Front. Cell Dev. Biol. 9:670960, 2021.

    Google Scholar 

  99. Ribatti, D., R. Tamma, and T. Annese. Epithelial-mesenchymal transition in cancer: a historical overview. Transl. Oncol. 13:100773, 2020.

    Google Scholar 

  100. Rinkenbaugh, A. L., and A. S. Baldwin. The NF-kappaB pathway and cancer stem cells. Cells. 5:16, 2016.

    Google Scholar 

  101. Sabatier, R., et al. Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization. Mol. Cancer. 13:228, 2014.

    Google Scholar 

  102. Sahlgren, C., M. V. Gustafsson, S. Jin, L. Poellinger, and U. Lendahl. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl. Acad. Sci. U.S.A. 105:6392–6397, 2008.

    Google Scholar 

  103. Santamaria, P. G., G. Moreno-Bueno, and A. Cano. Contribution of epithelial plasticity to therapy resistance. J. Clin. Med. 8:676, 2019.

    Google Scholar 

  104. Sareyeldin, R. M., et al. Gene expression and miRNAs profiling: function and regulation in Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. Cancers (Basel). 11:646, 2019.

    Google Scholar 

  105. Sari, I. N., et al. Hedgehog signaling in cancer: a prospective therapeutic target for eradicating cancer stem cells. Cells. 7:208, 2018.

    Google Scholar 

  106. Savan, R. Post-transcriptional regulation of interferons and their signaling pathways. J. Interferon Cytokine Res. 34:318–329, 2014.

    Google Scholar 

  107. Saxena, M., et al. AMP-activated protein kinase promotes epithelial-mesenchymal transition in cancer cells through Twist1 upregulation. J. Cell Sci. 131:jcs208314, 2018.

    Google Scholar 

  108. Schwerk, J., and R. Savan. Translating the untranslated region. J. Immunol. 195:2963–2971, 2015.

    Google Scholar 

  109. Scimeca, M., et al. Emerging prognostic markers related to mesenchymal characteristics of poorly differentiated breast cancers. Tumour Biol. 37:5427–5435, 2016.

    Google Scholar 

  110. Shao, S., et al. Notch1 signaling regulates the epithelial-mesenchymal transition and invasion of breast cancer in a Slug-dependent manner. Mol. Cancer. 14:28, 2015.

    Google Scholar 

  111. Shibue, T., and R. A. Weinberg. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14:611–629, 2017.

    Google Scholar 

  112. Singha, P. K., et al. Increased Smad3 and reduced Smad2 levels mediate the functional switch of TGF-beta from growth suppressor to growth and metastasis promoter through TMEPAI/PMEPA1 in triple negative breast cancer. Genes Cancer. 10:134–149, 2019.

    Google Scholar 

  113. Sun, Y., J. Zhang, and L. Ma. alpha-catenin. A tumor suppressor beyond adherens junctions. Cell Cycle. 13:2334–2339, 2014.

    Google Scholar 

  114. Talyor, M. A., J. G. Parvani, and W. P. Schiemann. The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells. J. Mammary Gland Biol. Neoplasia. 12:169–190, 2010.

    Google Scholar 

  115. Tam, S. Y., V. W. C. Wu, and H. K. W. Law. Hypoxia-induced epithelial-mesenchymal transition in cancers: HIF-1alpha and beyond. Front. Oncol. 10:486, 2020.

    Google Scholar 

  116. Tan, E. J., A. K. Olsson, and A. Moustakas. Reprogramming during epithelial to mesenchymal transition under the control of TGFbeta. Cell Adh. Migr. 9:233–246, 2015.

    Google Scholar 

  117. Testa, U., G. Castelli, and E. Pelosi. Breast cancer: a molecularly heterogenous disease needing subtype-specific treatments. Med. Sci. (Basel). 8:18, 2020.

    Google Scholar 

  118. Tian, M., and W. P. Schiemann. TGF-beta stimulation of EMT programs elicits non-genomic ER-alpha activity and anti-estrogen resistance in breast cancer cells. J. Cancer Metastasis Treat. 3:150–160, 2017.

    Google Scholar 

  119. Toft, D. J., and V. L. Cryns. Minireview: basal-like breast cancer: from molecular profiles to targeted therapies. Mol. Endocrinol. 25:199–211, 2011.

    Google Scholar 

  120. Tsai, J. H., and J. Yang. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 27:2192–2206, 2013.

    Google Scholar 

  121. Tzavlaki, K., and A. Moustakas. TGF-beta signaling. Biomolecules. 10:487, 2020.

    Google Scholar 

  122. Valastyan, S., and R. A. Weinberg. Tumor metastasis: molecular insights and evolving paradigms. Cell. 147:275–292, 2011.

    Google Scholar 

  123. Valenta, T., G. Hausmann, and K. Basler. The many faces and functions of beta-catenin. EMBO J. 31:2714–2736, 2012.

    Google Scholar 

  124. Wahdan-Alaswad, R., et al. Metformin attenuates transforming growth factor beta (TGF-beta) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer. Cell Cycle. 15:1046–1059, 2016.

    Google Scholar 

  125. Wang, M. M. Notch signaling and Notch signaling modifiers. Int. J. Biochem. Cell Biol. 43:1550–1562, 2011.

    Google Scholar 

  126. Wang, Z., Y. Li, D. Kong, and F. H. Sarkar. The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr. Drug Targets. 11:745–751, 2010.

    Google Scholar 

  127. Wang, W., S. A. Nag, and R. Zhang. Targeting the NFkappaB signaling pathways for breast cancer prevention and therapy. Curr. Med. Chem. 22:264–289, 2015.

    Google Scholar 

  128. Wang, Y., and B. P. Zhou. Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chin. J. Cancer. 30:603–611, 2011.

    Google Scholar 

  129. Warzecha, C. C., and R. P. Carstens. Complex changes in alternative pre-mRNA splicing play a central role in the epithelial-to-mesenchymal transition (EMT). Semin. Cancer Biol. 22:417–427, 2012.

    Google Scholar 

  130. Wei, X. L., et al. ERalpha inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer. Oncotarget. 6:21704–21717, 2015.

    Google Scholar 

  131. Wendt, M. K., T. M. Allington, and W. P. Schiemann. Mechanisms of the epithelial-mesenchymal transition by TGF-beta. Future Oncol. 5:1145–1168, 2009.

    Google Scholar 

  132. Wu, Y., et al. Decreased levels of active SMAD2 correlate with poor prognosis in gastric cancer. PLoS ONE. 7:e35684, 2012.

    Google Scholar 

  133. Wu, Y., M. Sarkissyan, and J. V. Vadgama. Epithelial-mesenchymal transition and breast cancer. J. Clin. Med. 5:13, 2016.

    Google Scholar 

  134. Wu, Y., and B. P. Zhou. TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br. J Cancer. 102:639–644, 2010.

    Google Scholar 

  135. Xu, Y., et al. Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expression. Oncogene. 36:1157–1166, 2017.

    Google Scholar 

  136. Xu, P., J. Liu, and R. Derynck. Post-translational regulation of TGF-beta receptor and Smad signaling. FEBS Lett. 586:1871–1884, 2012.

    Google Scholar 

  137. Xu, R., J. Y. Won, C. H. Kim, D. E. Kim, and H. Yim. Roles of the phosphorylation of transcriptional factors in epithelial-mesenchymal transition. J. Oncol. 2019:5810465, 2019.

    Google Scholar 

  138. Xu, X., M. Zhang, F. Xu, and S. Jiang. Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities. Mol. Cancer. 19:165, 2020.

    Google Scholar 

  139. Yam, C., S. A. Mani, and S. L. Moulder. Targeting the molecular subtypes of triple negative breast cancer: understanding the diversity to progress the field. Oncologist. 22:1086–1093, 2017.

    Google Scholar 

  140. Yang, J., et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 117:927–939, 2004.

    Google Scholar 

  141. Yang, J., and R. A. Weinberg. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell. 14:818–829, 2008.

    Google Scholar 

  142. Ye, Y., et al. ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene. 29:1451–1462, 2010.

    Google Scholar 

  143. Ye, L., et al. Functions and targets of miR-335 in cancer. Onco Targets Ther. 14:3335–3349, 2021.

    Google Scholar 

  144. Yuan, X., et al. Expression of Notch1 correlates with breast cancer progression and prognosis. PLoS ONE. 10:e0131689, 2015.

    Google Scholar 

  145. Zaravinos, A. The regulatory role of microRNAs in EMT and cancer. J. Oncol. 2015:865816, 2015.

    Google Scholar 

  146. Zarzynska, J. M. Two faces of TGF-beta1 in breast cancer. Mediators Inflamm. 2014:141747, 2014.

    Google Scholar 

  147. Zhang, J., et al. NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling. Oncotarget. 7:61036–61053, 2016.

    Google Scholar 

  148. Zhang, Y. E. Non-Smad Signaling Pathways of the TGF-beta Family. Cold Spring Harb Perspect Biol. 9:a022129, 2017.

    Google Scholar 

  149. Zhang, Y., P. B. Alexander, and X. F. Wang. TGF-beta family signaling in the control of cell proliferation and survival. Cold Spring. Harb. Perspect. Biol. 9:a022145, 2017.

    Google Scholar 

  150. Zhang, Z., L. Yao, J. Yang, Z. Wang, and G. Du. PI3K/Akt and HIF1 signaling pathway in hypoxiaischemia (Review). Mol. Med. Rep. 18:3547–3554, 2018.

    Google Scholar 

  151. Zhao, M., L. Ang, J. Huang, and J. Wang. MicroRNAs regulate the epithelial-mesenchymal transition and influence breast cancer invasion and metastasis. Tumour Biol. 39:1010428317691682, 2017.

    Google Scholar 

  152. Zhao, Z., M. A. Rahman, Z. G. Chen, and D. M. Shin. Multiple biological functions of Twist1 in various cancers. Oncotarget. 8:20380–20393, 2017.

    Google Scholar 

  153. Zheng, H., et al. Glycogen synthase kinase-3beta: a promising candidate in the fight against fibrosis. Theranostics. 10:11737–11753, 2020.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY, 13902, USA

    Busra Buyuk, Sha Jin & Kaiming Ye

Authors
  1. Busra Buyuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sha Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kaiming Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kaiming Ye.

Additional information

Associate Editor Michael R. King oversaw the review of this article.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Buyuk, B., Jin, S. & Ye, K. Epithelial-to-Mesenchymal Transition Signaling Pathways Responsible for Breast Cancer Metastasis. Cel. Mol. Bioeng. 15, 1–13 (2022). https://doi.org/10.1007/s12195-021-00694-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12195-021-00694-9

Keywords

Search

Navigation