Abstract
Purpose
Breast cancer is one of the most common female cancers. Moreover, despite the progress in medicine, its mortality rate is still very high. Therefore, researchers are constantly looking for new prognostic factors, which may simplify disease diagnosis and optimize the therapy. Metastases are responsible for the majority of deaths caused by breast cancer. Epithelial-mesenchymal transition is one of the mechanisms of metastasis, which is controlled by specific transcription factors. In the recent years, many researchers studied the prognostic value of factors promoting the epithelial–mesenchymal transition in patients with breast cancer. This work is an attempt to summarize the current state of knowledge on this issue.
Methods
A systemic search of peer-reviewed articles published between November 2005 and February 2016 was performed using PubMed/MEDLINE database. Most cited articles constituted original papers, although single review articles were also included.
Results
Based on the so far conducted studies, a promising conclusion can be drawn, that several described factors might serve as a putative negative prognostic marker in breast cancer.
Conclusions
Obtained results of this review should encourage researchers to conduct further clinical trials on large patient groups which will evaluate the prognostic value of EMT transcription factors in breast cancer course.
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References
International Agency for Research on Cancer Press Release No. 223. 2012. https://www.iarc.fr/en/media-centre/pr/2013/pdfs/pr223_E.pdf. Accessed 04 Apr 2016
Kumar P, Aggarwal R (2016) An overview of triple-negative breast cancer. Arch Gynecol Obstet 293:247–269
Gonzalez DM, Medici D (2014) Signaling mechanisms of the epithelial-mesenchymal transition. Sci. Signal 7:8
Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition J Clin Invest 119:1420–1428
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890
Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nas Rev. Mol Cell Biol 15:178–196
Pieniążek M, Donizy P, Ziętek M, Szynglarewicz B, Matkowski R (2012) The role of TGF-β-related signal transduction pathways in pathogenesis of epithelial-mesenchymal transition as a key element in cancer development and progression. Postepy Hig Med Dosw 66:583–591
Wu Y, Zhou BP (2010) Snail—more than EMT. Cell Adh Migr 4:199–203
Wang Y, Shi J, Chai K, Ying X, Zhou BP (2013) The role of snail in EMT and tumorigenesis. Curr Cancer Drug Targets 13:963–972
Muenst S, Däster S, Obermann EC, Droeser RA, Weber WP, von Holzen U et al (2013) Nuclear expression of snail is an independent negative prognostic factor in human breast cancer. Dis Markers 35:337–344
Yang Z, Zhang B, Liu B, Xie Y, Cao X (2015) Combined Runx2 and Snail overexpression is associated with a poor prognosis in breast cancer. Tumour Biol 36:4565–4573
ElMoneim HM, Zaghloul NM (2011) Expression of E-cadherin, N-cadherin and snail and their correlation with clinicopathological variants: an immunohistochemical study of 132 invasive ductal breast carcinomas in Egypt. Clinics 66:1765–1771
Jiralerspong S, Liu S, Palla SL, Mills GB, Hung M, Hortobagyi GN et al (2010) Correlation of Snail expression and survival in patients with early-stage triple-negative breast cancer (TNBC). J Clin Oncol 28:15
Wu ZQ, Li XY, Hu CY, Ford M, Kleer CG, Weiss SJ (2012) Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression. Proc Natl Acad Sci USA 109:16654–16659
Shao S, Zhao X, Zhang X, Luo M, Zuo X, Huang S et al (2015) Notch1 signaling regulates the epithelial–mesenchymal transition and invasion of breast cancer in a Slug-dependent manner. Mol Cancer 14:28
Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM et al (2005) Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123:641–653
Li Y, Wu Y, Abbatiello TC, Wu WL, Kim JR, Sarkissyan M et al (2015) Slug contributes to cancer progression by direct regulation of ERα signaling pathway. Int J Oncol 46:1461–1472
El-Seaidy AZ, El-Osaily GM, Youssef SA, El-Balshy A, Absalla MS (2015) Prognostic value of epithelial mesenchymal transition (EMT&Slug) markers in ductal carcinoma of the breast. Med. J. Cairo. Univ 83:1–11
Liu T, Zhang X, Shang M, Zhang Y, Xia B, Niu M et al (2013) Dysregulated expression of Slug, vimentin, and E-kadherin correlates with poor clinical outcome in patients with basal-like breast cancer. J Surg Oncol 107:188–194
Sanchez-Tillo E, Siles L, de Barrios O, Cuatrecasas M, Vaquero EC, Castells A et al (2012) Expanding roles of ZEB factors in tumorogenesis and tumor progression. Am J Cancer Res 2:897–912
Schmalhofer O, Brabletz S, Brabletz T (2009) E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev 28:151–166
Soini Y, Tuhkanen H, Sironen R, Virtanen I, Kataja V, Auvinen P et al (2011) Transcription factors zeb1, twist and snai1 in breast carcinoma. BMC Cancer 11:73
Xiang S, Liu YM, Chen X, Wang YW, Ma RR, Wu XJ et al (2015) ZEB1 expression is correlated with tumor metastasis and reduced prognosis of breast carcinoma in Asian patients. Cancer Invest 33:225–231
Jang MH, Kim HJ, Kim EJ, Chung YR, Park SY (2015) Expression of epithelial-mesenchymal transition-related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome. Hum Pathol 46:1267–1274
Jouppila-Mättö A, Mannermaa A, Sironen R, Kosma VM, Soini Y, Pukkila M (2015) SIP1 predicts progression and poor prognosis in pharyngeal squamous cell carcinoma. Histol Histopathol 30:569–579
Bhardwaj M, Sen S, Sharma A, Kashyap S, Chosdol K, Pushker N et al (2015) ZEB2/SIP1 as novel prognostic indicator in eyelid sebaceous gland carcinoma. Hum Pathol 46:1437–1442
Miura N, Yano T, Shoji F, Kawano D, Takenaka T, Ito K et al (2009) Clinicopathological significance of Sip1-associated epithelial mesenchymal transition in non-small cell lung cancer progression. Anticancer Res 29:4099–4106
Sayan AE, Griffiths TR, Pal R, Browne GJ, Ruddick A, Yagci T et al (2009) SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. Proc Natl Acad Sci USA 106:14884–14889
Wang X, Lu H, Urvalek AM, Li T, Yu L, Lamar J et al (2011) KLF8 promotes human breast cancer cell invasion and metastasis by transcriptional activation of MMP9. Oncogene 30:1901–1911
Wang CX (2013) Krüppel-like factor 8 overexpression is correlated with angiogenesis and poor prognosis in gastric cancer. World J Gastroenterol 19:4309–4315
Yingxin W, Ge C, Lei Y, Yupei Z (2014) Krüppel-like factor 8 is a potential prognostic factor for pancreatic cancer. Chin Med J 127:856–859
Li JC, Yang XR, Sun HX, Xu Y, Zhou J, Qiu SJ (2010) Up-regulation of Kruppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma. Gastroenterology 139:2146–2157
Khan MA, Chen HC, Zhang D, Fu J (2013) Twist: a molecular target in cancer therapeutics. Tumour Biol 34:2497–2506
Li J, Zhou B (2011) Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer 11:49
Hong J, Zhou J, Fu J, He T, Qin J, Wang L et al (2011) hosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res 71:3980–3990
Vesuna F, Lisok A, Kimble B, Domek J, Kato Y, van der Groep P et al (2012) Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-α. Oncogene 31:3223–3234
Mao Y, Zhang N, Xu J, Ding Z, Zong R, Liu Z (2012) Significance of heterogeneous Twist2 expression in human breast cancers. PLoS One 7:e48178
Fang X, Cai Y, Liu J, Wang Z, Wu Q, Zhang Z et al (2011) Twist2 contributes to breast cancer progression by promoting an epithelial-mesenchymal transition and cancer stem-like cell self-renewal. Oncogene 30:4707–4720
Zhao M, Hong-Guang H, Huang J, Zou Q, Wang J, Liu MQ et al (2013) Expression and correlation of Twist and gelatinases in breast cancer. Exp Ther Med 6:97–100
Xu Y, Hu B, Qin L, Zhao L, Wang Q, Wang Q et al (2014) SRC-1 and Twist1 expression positively correlates with a poor prognosis in human breast cancer. Int J Biol Sci 10:396–403
Zhang YQ, Wei XL, Liang YK, Chen WL, Zhang F, Bai JW et al (2015) Over-expressed twist associates with markers of epithelial mesenchymal transition and predicts poor prognosis in breast cancers via ERK and Akt activation. PLoS One 10:e0135851
Riaz M, Sieuwerts AM, Look MP, Timmermans MA, Smid M, Foekens JA et al (2012) High TWIST1 mRNA expression is associated with poor prognosis in lymph node-negative and estrogen receptor-positive human breast cancer and is co-expressed with stromal as well as ECM related genes. Breast Cancer Res 14:R123
van Nes JG, de Kruijf EM, Putter H, Faratian D, Munro A, Campbell F et al (2012) Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients. Breast Cancer Res Treat 133:49–59
Grzegrzolka J, Biala M, Wojtyra P, Kobierzycki C, Olbromski M, Gomulkiewicz A et al (2015) Expression of EMT Markers SLUG and TWIST in Breast Cancer. Anticancer Res 35:3961–3968
Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N et al (2007) Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA 104:10069–10074
Hader C, Marlier A, Cantley L (2010) Mesenchymal-Epithelial Transition in epithelial response to injury: the role of Foxc2. Oncogene 29:1031–1040
Han B, Qu Y, Jin Y, Yu Y, Deng N, Wawrowsky K et al (2015) FOXC1 activates smoothened-independent hedgehog signaling in basal-like breast cancer. Cell Rep 13:1046–1058
Wang J, Ray PS, Sim MS, Zhou XZ, Lu KP, Lee AV et al (2012) FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling. Oncogene 31:4798–4802
Ray PS, Bagaria SP, Wang J, Shamonki JM, Ye X, Sim MS et al (2011) Basal-like breast cancer defined by FOXC1 expression offers superior prognostic value: a retrospective immunohistochemical study. Ann Surg Oncol 18:3839–3847
Ray PS, Wang J, Qu Y, Sim MS, Shamonki J, Bagaria SP et al (2010) FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res 70:3870–3876
Lim JC, Koh VC, Tan JS, Tan WJ, Thike AA, Tan PH (2015) Prognostic significance of epithelial-mesenchymal transition proteins Twist and Foxc2 in phyllodes tumours of the breast. Breast Cancer Res Treat 150:19–29
Dai J, Wang JY, Yang LL, Xiao Y, Qu ZL, Qin SH et al (2014) Correlation of Forkhead Box c2 with subtypes and invasive ability of invasive breast cancer. J Huazhong Univ Sci Technolog Med Sci 34:896–901
Micalizzi DS, Wang CA, Farabaugh SM, Schiemann WP, Ford HL (2010) Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth. Cancer Res 70:10371–10380
Iwanaga R, Wang CA, Micalizzi DS, Harrell JC, Jedlicka P, Sartorius CA et al (2012) Expression of Six1 in luminal breast cancers predicts poor prognosis and promotes increases in tumor initiating cells by activation of extracellular signal-regulated kinase and transforming growth factor-beta signaling pathways. Breast Cancer Res 14:R100
Xu H, Zhang Y, Altomare D, Peña MM, Wan F, Pirisi L et al (2014) Six1 promotes epithelial-mesenchymal transition and malignant conversion in human papillomavirus type 16-immortalized human keratinocytes. Carcinogenesis 35:1379–1388
Wang CA, Jedlicka P, Patrick AN, Micalizzi DS, Lemmer KC, Deitsch E et al (2012) SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer. J Clin Invest 122:1895–1906
Jin H, Cui M, Kong J, Cui X, Lin Z, Wu Q et al (2014) Sineoculis homeobox homolog 1 protein is associated with breast cancer progression and survival outcome. Exp Mol Pathol 97:247–252
Tan WJ, Thike AA, Bay BH, Tan PH (2014) Immunohistochemical expression of homeoproteins Six1 and Pax3 in breast phyllodes tumours correlates with histological grade and clinical outcome. Histopathology 64:807–817
Yu M, Smolen GA, Zhang J, Wittner B, Schott BJ, Brachtel E et al (2009) A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes Dev 23:1737–1742
Hartwell KA, Muir B, Reinhardt F, Carpenter AE, Sgroi DC, Weinberg RA (2006) The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc Natl Acad Sci USA 103:18969–18974
Kang KW, Lee MJ, Song JA, Jeong JY, Kim YK, Lee C et al (2014) Overexpression of goosecoid homeobox is associated with chemoresistance and poor prognosis in ovarian carcinoma. Oncol Rep 32:189–198
Xue TC, Ge NL, Zhang L, Cui JF, Chen RX, You Y et al (2014) Goosecoid promotes the metastasis of hepatocellular carcinoma by modulating the epithelial-mesenchymal transition. PLoS One 9:e109695
Acknowledgements
This project was financed from the funds of National Science Centre Granted by decision No. DEC-2015/19/N/NZ7/03071.
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MM—data analysis, manuscript writing, LKS—data analysis, manuscript writing, BJJ—data analysis, manuscript writing, MK—data analysis, manuscript writing.
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Matysiak, M., Kapka-Skrzypczak, L., Jodłowska-Jędrych, B. et al. EMT promoting transcription factors as prognostic markers in human breast cancer. Arch Gynecol Obstet 295, 817–825 (2017). https://doi.org/10.1007/s00404-017-4304-1
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DOI: https://doi.org/10.1007/s00404-017-4304-1