Document Type : Review Article
Authors
1 Department of Biology, Gaziantep University, Gaziantep, Turkey Farabi Molecular Laboratory, Irbil, Iraq
2 Department of Biology, Gaziantep University, Gaziantep, Turkey
Abstract
One of the key molecular mechanisms contributing to the metastatic progression is epithelial to mesenchymal transition (EMT), which drives invasion and migration of various cancer including breast cancer.During tumorigenesis, changes in EMT regulatory pathways lead to a loss of cellular adhesions, changes in the polarization of the cell and cytoskeleton, detachment, migration, intra-vasation, and survival in the vascular system; extravasation, and finally, metastasis.EMT is largely mediated by a core set of EMT-activating transcription factors. The master regulators of the EMT include many pathways, however the primary mediators of the EMT include signaling through TGF-, Notch and Wnt. The role of EMT in breast cancer has been demonstrated via numerous in vitro studies in normal and malignant mammary epithelial cells and via in vivo studies using mouse models of breast cancers. Studying the regulatory pathways of the EMT process can be used as a tool for cancer monitoring ,treatment and possible direct targets for new-combination anticancer personalized medicine.
Keywords
- Prat, A.; Perou, C.M. Desconstructing the molecular portraits of
breast cancer. Mol. Oncol. 2011, 5, 5–23.
2. Taube, J.H.; Herschkowitz, J.I.; Komurov, K.; Zhou, A.Y.;
Gupta, S.; Yang, J.; Hartwell, K.; Onder, T.T.; Gupta, P.B.;
Evans, K.W.; et al. Core epithelial-to-mesenchymal transition
interactome gene-expression signature is associated with claudin-
low and metaplastic breast cancer subtypes. Proc. Natl. Acad. Sci.
USA 2010, 107, 15449–15454.
3. Micalizzi, D.; Ford, H. Epithelial to mesenchymal transition in
development of cancer. Future Oncol. 2009, 8,1129–1143. J. Clin.
Med. 2016, 5, 6512 of 14
4. Scimeca, M.; Antonacci, C.; Colombo, D.; Bonfiglio, R.;
Buonomo, O.C.; Bonanno, E. Emerging prognostic markers
related to mesenchymal characteristics of poorly differentiated
breast cancers. Tumor Biol. 2016, 37, 5427–5435.
5. Polyak, K.; Weinberg, R.A. Transitions between epithelial and
mesenchymal states: Acquisition of malignant and stem cell traits.
Nat. Rev. 2009, 9, 265–273.
6. Taylor, M.A.; Parvani, J.G.; Schiemann, W.P. The
pathophysiology of epithelial-mesenchymal transition induced by
transforming growth factor- in normal and malignant mammary
epithelial cells. J. Mammary Gland Biol. Neoplasia 2010, 15,
169–190.
7. Sarrió, D.; Rodriguez-Pinilla, S.M.; Hardisson, D.; Cano, A.;
Moreno-Bueno, G.; Palacios, J.Epithelial-Mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res.
2008, 68, 989–997.
8. Lien, H.C.; Hsiao, Y.H.; Lin, Y.S.; Yao, Y.T.; Juan, H.F.;
Kuo, W.H.; Hung, M.C.; Chang, K.J.; Hsieh, F.J. Molecular
signatures of metaplastic carcinoma of the breast by large-scale
transcriptional profiling: Identification of genes potentially related
to epithelial-mesenchymal transition. Oncogene 2007, 26, 7859–
7871.
9. Al Saleh, S.; Al Mulla, F.; Luqmani, Y.A. Estrogen receptor
silencing induces epithelial to mesenchymal transition in human
breast cancer cells. PLoS ONE 2011, 6, e20610.
10. Pomp, V.; Leo, C.; Mauracher, A.; Korol, D.; Guo, W.; Varga,
Z. Differential expression of epithelial-mesenchymal transition
and stem cell markers in intrinsic subtypes of breast cancer. Breast
Cancer Res. Treat. 2015, 154, 45–55.
11. Czerwinska, P.; Kaminska, B. Regulation of breast cancer
stem cell features. Contemp. Oncol. 2015, 19, A7–A15.
12. Coradini, D.; Boracchi, P.; Ambrogi, F.; Biganzoli, E.; Oriana,
S. Cell polarity. Epithelial-mesenchymal transition and cell-fate
decision gene expression in ductal carcinoma in situ. Int. J. Surg.
Oncol. 2012, 2012, 984346.
13. Wang, Y.; Zhou, B.P. Epithelial-mesenchymal transition—A
hallmark of breast cancer metastasis. Cancer Hallm. 2013, 1,
38–49.
14. Knudsen, E.S.; Ertel, A.; Davicioni, E.; Kline, J.; Schwartz,
G.F.; Witkiewicz, A.K. Progression of ductal carcinoma in situ
to invasive breast cancer is associated with gene expression
programs of EMT and myoepithelial. Breast Cancer Res. Treat.
2012, 133, 1009–1024.
15. Bouris, P.; Skandalis, S.S.; Piperigkou, Z.; Afratis, N.;
Karamanou, K.; Aletras, A.J.; Moustakas, A.; Theocharis, A.D.;
Karamanos, N.K. Estrogen receptor alpha mediates epithelial to
mesenchymal transition, expression of specific matrix effectors
and functional properties of breast cancer cells. Matrix Biol. 2015,
43, 42–60.
16. Radisky, E.; Radisky, D. Matrix metalloproteinase-induced
epithelial-mesenchymal transition in breast cancer. J. Mammary
Gland Biol. Neoplasia 2012, 15, 201–212.
17. Cichon, M.A.; Nelson, C.M.; Radisky, D.C. Regulation of
epithelial-mesenchymal transition in breast cancer cells by cell
contact and adhesion. Cancer Inform. 2015, 14 (Suppl. 3), 1–13.
18. Faronato, M.; Nguyen, V.T.; Patten, D.K.; Lombardo, Y.; Steel,
J.H.; Patel, N.; Woodley, L.; Shousha, S.; Pruneri, G.; Coombes,
R.C.; et al. DMXL2 drives epithelial to mesenchymal transition
in hormonal therapy resistant breast cancer through notch hyper-
activation. Oncotarget 2015, 6, 22467–22479.
19. Fischer, K.; Durrans, A.; Lee, S.; Sheng, J.; Li, F.; Wong, S.T.;
Choi, H.; El Rayes, T.; Ryu, S.; Troeger, J.; et al. Epithelial-to-
mesenchymal transition is not required for lung metastasis but
contributes to chemoresistance. Nature 2015, 527, 472–476.
20. Lombaerts, M.; van Wezel, T.; Philippo, K.; Dierssen, J.W.;
Zimmerman, R.M.; Oosting, J.; van Eijk, R.; Eilers, P.H.; van
de Water, B.; Cornelisse, C.J.; et al. E-cadherin transcriptional
downregulation by promoter methylation but not mutation is
related to epithelial-to-mesenchymal transition in breast cancer
cell lines. Br. J. Cancer 2006, 94, 661–671.
21. Ciriello, G.; Gatza, M.L.; Beck, A.H.; Wilkerson, M.D.; Rhie,
S.K.; Pastore, A.; Zhang, H.; McLellan, M.; Yau, C.; Kandoth,
C.; et al. Comprehensive molecular portraits of invasive lobular
breast cancer. Cell 2015, 163, 506–519 J. Clin. Med. 2016, 5, 65
13 of 14
22. Onder, T.T.; Gupta, P.B.; Mani, S.A.; Yang, J.; Lander, E.S.;
Weinberg, R.A. Loss of E-cadherin promotes metastasis via
multiple downstream transcriptional pathways. Cancer Res. 2008,
68, 3645–3654.
23. Thomson, S.; Petti, F.; Sujka-Kwok, I.; Mercado, P.; Bean,
J.; Monaghan, M.; Seymour, S.L.; Argast, G.M.; Epstein, D.M.;
Haley, J.D. A system view of epithelial-mesenchymal transition
signaling states. Clin. Exp. Metastasis 2011, 28, 137–155.
[CrossRef] [PubMed]
24. Abdulla, T.; Luna-Zurita, L.; de la Pompa, J.L.; Schleich, J.M.;
Summers, R. Epithelial to mesenchymal transition—The roles of
cell morphology, labile adhesion and junctional coupling. Comput
Methods Progr. Biomed. 2013.
25. Katz, E.; Dubois-Marshall, S.; Sims, A.H.; Gautier, P.;
Caldwell, H.; Meehan, R.R.; Harrison, D.J. An in vitro model that
recapitulates the epithelial to mesenchymal transition (EMT) in
human breast cancer. PLoS ONE 2001, 6, e17083.
26. Nelson, W.J.; Nusse, R. Convergence of Wnt, beta-catenin,
and cadherin pathways. Science 2004, 303, 1483–1487.
27. Geyer, F.C.; Lacroix-Triki, M.; Savage, K.; Arnedos, M.;
Lambros, M.B.; MacKay, A.; Natrajan, R.; Reis-Filho, J.S.
-catenin pathway activation in breast cancer is associated with
triple-negative phenotype but not with CTNNB1 mutation. Mod.
Pathol. 2011, 24, 209–231.
28. Mukherjee, N.; Panda, C. Subtype-specific alterations of
the Wnt signaling pathway in breast cancer. Clin. Progn. Signif.
Cancer Sci. 2012, 103, 210–220.
29. Li, Y.; Wang, Z. Regulation of EMT by Notch signaling
pathway in tumor progression. Curr. Cancer Drug Targets 2013,
13, 957–962.
30. Farnie, G.; Clarke, R. Mammary stem cells and breast cancer—
Role of Notch signaling. Stem Cell Rev. 2007, 3, 169–175.
31. Yuan, X.; Zhang, M.; Wu, H.; Xu, H.; Han, N.; Chu, Q.;
Yu, S.; Chen, Y.; Wu, K. Expression of Notch 1 correlates with
breast cancer progression and prognosis. PLoS ONE 2015, 10,
e0131689.
32. Liu, Z.J.; Semenza, G.L.; Zhang, H.F. Hypoxia-inducible
factor 1 and breast cancer metastasis. Biomed. Biotechnol. 2015,
16, 32–43.
33. Aiwei, Y.; Kieber-Emons, T. Adipocyte hypoxia causes
epithelial to mesenchymal transition—Related gene expression
and estrogen receptor-negative phenotype in breast cancer cells.
Oncol. Rep. 2015, 33, 2689–2694.
34. Ho, M.Y.; Tang, S.J.; Chuang, M.J.; Cha,
T.L.; Li, J.Y.; Sun, G.H.; Sun, K.H. TNF-
induces epithelial-mesenchymal transition of renal cell carcinoma
cells via a GSK3-dependent mechanism. Mol. Cancer Res. 2012,
10, 1109–1119.
35. Li, C.W.; Xia, W.; Huo, L.; Lim, S.O.; Wu, Y.; Hsu,
J.L.; Chao, C.H.; Yamaguchi, H.; Yang, N.K.; Ding, Q.;
et al. Epithelial-mesenchymal transition induced by TNF-
requires NF-B-mediated transcriptional upregulation of Twist 1.
Cancer Res. 2012, 72, 1290–1300.
36. Iorio, M.; Ferracin, M.; Liu, C.G.; Veronese, A.; Spizzo, R.;
Sabbioni, S.; Magri, E.; Pedriali, M.; Fabbri, M.; Campiglio, M.;
et al. MicroRNA gene expression deregulation in human breast
cancer. Cancer Res. 2005, 65,7065–7070.
37. Kimelman D, Xu W. β-Catenin destruction complex: insights
and questions from a structural perspective. Oncogene. 2006
Dec;25(57):7482-91.
38. Creighton, C.J.; Gibbons, D.L.; Kurie, J.M. The role of
epithelial-mesenchymal transition programming in invasion and
metastasis: A clinical perspective. Cancer Manag. Res. 2013, 5,
187–195.
39. Guttilla, I.; White, B. ER , microRNAs, and the epithelial-mesenchymal transition in breast cancer. Trends Endocrinol.
Metab. 2012, 3, 73–82.
40. Yu, J.; Xie, F.; Bao, X.; Chen, W.; Xu, Q. miR-300 inhibits
epithelial to mesenchymal transition and metastasis by targeting
Twist in human epithelial cancer. Mol. Cancer 2014, 13, 121.
41. Lin, Y.; Dong, C.; Zhou, B.P. Epigenetic regulation of EMT:
The snail story. Curr. Pharm. Des. 2014, 20, 1698–1705.
42. Sigurdsson, V.; Gudjonsson, T. Endothelial induced EMT in
breast epithelial cells with stem cells properties. PLoS ONE 2011,
6, e23833. J. Clin. Med. 2016, 5, 65 14 of 14
43. Wendt, M.K.; Schiemann, W.P. Mechanisms of epithelial-
mesenchymal transition by TGF-. Future Oncol.2009, 5, 1145–
1168.
44. Kalluri, R.; Wienberg, R.A. The basics of epithelial-mesen-
chymal transition. J. Clin. Investig. 2009, 119,1420–1428.
45. Groger, C.; Grubinger, M.; Waldhör, T.; Vierlinger, K.; Miku-
lits, W. Meta-analysis of gene expression signatures defining the
epithelial to mesenchymal transition during cancer progression.
PLoS ONE 2012, 7, e51136.
)