Oncogenic roles of EMT-inducing transcription factors

Nature Cell Biology

Volumn 16, Issue 6, 2014, Pages 488-494

  Puisieux, Alain ^a,b,c   Brabletz, Thomas ^d,e   Caramel, Julie ^a,b,c  

^a CENTRE DE RECHERCHE EN CANCÉROLOGIE DE LYON   (France)

^b UNIVERSITÉ LYON 1   (France)

^c CENTRE LÉON BÉRARD   (France)

^d UNIVERSITY OF FREIBURG   (Germany)

^e GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

PROTEIN MDM2; PROTEIN P53; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR SLUG; TRANSCRIPTION FACTOR ZEB1;

CANCER CELL; CANCER STEM CELL; CARCINOGENESIS; CELL DIFFERENTIATION; EPIGENETICS; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIUM CELL; HUMAN; INVASIVE CARCINOMA; MALIGNANT TRANSFORMATION; MELANOMA; METASTASIS; NONHUMAN; ONCOGENE; PRECANCER; PRIORITY JOURNAL; REVIEW; TUMOR GROWTH; TUMOR INVASION; TUMOR MICROENVIRONMENT;

ANIMALS; CELL DIFFERENTIATION; CELL TRANSFORMATION, NEOPLASTIC; EPITHELIAL-MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASM INVASIVENESS; NEOPLASMS; NEOPLASTIC STEM CELLS; ONCOGENE PROTEINS; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TUMOR MICROENVIRONMENT; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84901787644     PISSN: 14657392     EISSN: 14764679     Source Type: Journal    
DOI: 10.1038/ncb2976     Document Type: Review

References (137)

1. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890 (2009).
2. Nieto, M. A. Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342, 1234850 (2013).
3. Tam, W. L. & Weinberg, R. A. The epigenetics of epithelial- mesenchymal plasticity in cancer. Nat. Med. 19, 1438-1449 (2013).
4. Rowe, R. G. et al. Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs. J. Cell Biol. 184, 399-408 (2009).
5. Arnoux, V., Nassour, M., L'Helgoualc'h, A., Hipskind, R. A. & Savagner, P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol. Biol. Cell 19, 4738-4749 (2008).
6. Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415-428 (2007). (Pubitemid 46809165)
7. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341-350 (2002). (Pubitemid 34847966)
8. Brabletz, T. et al. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc. Natl. Acad. Sci. USA 98, 10356-10361 (2001). (Pubitemid 32803024)
9. Scheel, C., Onder, T., Karnoub, A. & Weinberg, R. A. Adaptation versus selection: the origins of metastatic behavior. Cancer Res. 67, 11476-11479 (2007).
10. Brabletz, T. To differentiate or not-routes towards metastasis. Nat. Rev. Cancer 12, 425-436 (2012).
11. De Craene, B. & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97-110 (2013).
12. Hugo, H. et al. Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J. Cell Physiol. 213, 374-383 (2007). (Pubitemid 47509716)
13. Morel, A. P. et al. EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLoS. Genet. 8, e1002723 (2012).
14. Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275-292 (2011).
15. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest 119, 1420-1428 (2009).
16. Aigner, K. et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26, 6979-6988 (2007). (Pubitemid 350014612)
17. Cordenonsi, M. et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147, 759-772 (2011).
18. Spaderna, S. et al. The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res. 68, 537-544 (2008). (Pubitemid 351380082)
19. Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725-736 (2012).
20. Spaderna, S. et al. A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology 131, 830-840 (2006). (Pubitemid 44307069)
21. Yokobori, T. et al. Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis. Cancer Res. 73, 2059-2069 (2013).
22. Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580-584 (2013).
23. Bednarz-Knoll, N., Alix-Panabieres, C. & Pantel, K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metast. Rev. 31, 673-687 (2012).
24. Smit, M. A., Geiger, T. R., Song, J. Y., Gitelman, I. & Peeper, D. S. A Twist-Snail axis critical for TrkB-induced epithelial-mesenchymal transition-like transformation, anoikis resistance, and metastasis. Mol. Cell Biol. 29, 3722-3737 (2009).
25. Labelle, M., Begum, S. & Hynes, R. O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20, 576-590 (2011).
26. Chaffer, C. L. et al. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 66, 11271-11278 (2006). (Pubitemid 46009956)
27. Korpal, M. et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat. Med. 17, 1101-1108 (2011).
28. Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709-724 (2012).
29. Vega, S. et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131-1143 (2004). (Pubitemid 38669034)
30. Scheel, C. & Weinberg, R. A. Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells? Int. J. Cancer 129, 2310-2314 (2011).
31. Klymkowsky, M. W. & Savagner, P. Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. Am. J. Pathol. 174, 1588-1593 (2009).
32. Tam, W. L. et al. Protein kinase C alpha is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 24, 347-364 (2013).
33. Husemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58-68 (2008). (Pubitemid 350309740)
34. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349-361 (2012).
35. Geradts, J. et al. Nuclear Snail1 and nuclear ZEB1 protein expression in invasive and intraductal human breast carcinomas. Hum. Pathol. 42, 1125-1131 (2011).
36. Mironchik, Y. et al. Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res. 65, 10801-10809 (2005). (Pubitemid 41715228)
37. Montserrat, N. et al. Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma. Hum. Pathol. 43, 632-643 (2012).
38. Sarrio, D. et al. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68, 989-997 (2008). (Pubitemid 351272216)
39. Matsumoto, T. et al. Loss of heterozygosity analysis shows monoclonal evolution with frequent genetic progression and divergence in esophageal carcinosarcoma. Hum. Pathol. 35, 322-327 (2004). (Pubitemid 38339606)
40. Castilla, M. A. et al. Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma. J. Pathol. 223, 72-80 (2011).
41. Spoelstra, N. S. et al. The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers. Cancer Res. 66, 3893-3902 (2006).
42. Trimboli, A. J. et al. Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res. 68, 937-945 (2008). (Pubitemid 351206773)
43. Damonte, P., Gregg, J. P., Borowsky, A. D., Keister, B. A. & Cardiff, R. D. EMT tumorigenesis in the mouse mammary gland. Lab. Invest. 87, 1218-1226 (2007). (Pubitemid 350126707)
44. Santisteban, M. et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 69, 2887-2895 (2009).
45. Prat, A. et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12, R68 (2010).
46. Prat, A. & Perou, C. M. Deconstructing the molecular portraits of breast cancer. Mol. Oncol. 5, 5-23 (2011).
47. Hennessy, B. T. et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116-4124 (2009).
48. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 (2008). (Pubitemid 351636299)
49. Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178-196 (2014).
50. Lopez-Novoa, J. M. & Nieto, M. A. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol. Med. 1, 303-314 (2009).
51. Desprat, N., Supatto, W., Pouille, P. A., Beaurepaire, E. & Farge, E. Tissue deformation modulates twist expression to determine anterior midgut differentiation in Drosophila embryos. Dev. Cell 15, 470-477 (2008).
52. Dong, C. et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 23, 316-331 (2013).
53. Shin, S., Dimitri, C. A., Yoon, S. O., Dowdle, W. & Blenis, J. ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. Mol. Cell 38, 114-127 (2010).
54. Ansieau, S., Morel, A. P., Hinkal, G., Bastid, J. & Puisieux, A. TWISTing an embryonic transcription factor into an oncoprotein. Oncogene 29, 3173-3184 (2010).
55. Ansieau, S. et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 14, 79-89 (2008). (Pubitemid 351890463)
56. Maestro, R. et al. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 13, 2207-2217 (1999). (Pubitemid 29426726)
57. Valsesia-Wittmann, S. et al. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell 6, 625-630 (2004). (Pubitemid 40017705)
58. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602 (1997). (Pubitemid 27152402)
59. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864-870 (2005). (Pubitemid 40558993)
60. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725-730 (2005). (Pubitemid 41117277)
61. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907-913 (2005). (Pubitemid 40559004)
62. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005). (Pubitemid 41117258)
63. Piccinin, S. et al. A "twist box" code of p53 inactivation: twist box: p53 interaction promotes p53 degradation. Cancer Cell 22, 404-415 (2012).
64. Liu, Y., El-Naggar, S., Darling, D. S., Higashi, Y. & Dean, D. C. Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development 135, 579-588 (2008).
65. Ohashi, S. et al. Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors. Cancer Res. 70, 4174-4184 (2010).
66. Swarbrick, A., Roy, E., Allen, T. & Bishop, J. M. Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response. Proc. Natl. Acad. Sci. USA 105, 5402-5407 (2008). (Pubitemid 351753875)
67. Wu, W. S. et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123, 641-653 (2005).
68. Lee, S. H. et al. Blocking of p53-Snail binding, promoted by oncogenic K-Ras, recovers p53 expression and function. Neoplasia 11, 22-31 (2009).
69. Kajita, M., McClinic, K. N. & Wade, P. A. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol. Cell Biol. 24, 7559-7566 (2004). (Pubitemid 39121483)
70. Pallier, K. et al. TWIST1 a new determinant of epithelial to mesenchymal transition in EGFR mutated lung adenocarcinoma. PLoS One 7, e29954 (2012).
71. Tran, P. T. et al. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis. PLoS Genet. 8, e1002650 (2012).
72. Olmeda, D. et al. SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells. Cancer Res. 67, 11721-11731 (2007).
73. Olmeda, D. et al. Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines. Oncogene 27, 4690-4701 (2008).
74. De, C. B. et al. Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential. Cell Death. Differ. 21, 310-320 (2013).
75. Knudson, A. G. Stem cell regulation, tissue ontogeny, and oncogenic events. Semin. Cancer Biol. 3, 99-106 (1992).
76. Scotting, P. J., Walker, D. A. & Perilongo, G. Childhood solid tumours: a developmental disorder. Nat. Rev. Cancer 5, 481-488 (2005). (Pubitemid 40791490)
77. Dick, J. E. Stem cell concepts renew cancer research. Blood 112, 4793-4807 (2008).
78. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645-648 (1994). (Pubitemid 24067706)
79. Morel, A. P. et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 3, e2888 (2008).
80. Vesuna, F., Lisok, A., Kimble, B. & Raman, V. Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. Neoplasia 11, 1318-1328 (2009).
81. Taube, J. H. 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 107, 15449-15454 (2010).
82. McCoy, E. L. et al. Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. J. Clin. Invest 119, 2663-2677 (2009).
83. Micalizzi, D. S. et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J. Clin. Invest 119, 2678-2690 (2009).
84. Yang, M. H. et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat. Cell Biol. 12, 982-992 (2010).
85. Wellner, U. et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11, 1487-1495 (2009).
86. Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138, 592-603 (2009).
87. Guo, W. et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 148, 1015-1028 (2012).
88. Chaffer, C. L. et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154, 61-74 (2013).
89. Brabletz, T. EMT and MET in metastasis: where are the cancer stem cells? Cancer Cell 22, 699-701 (2012).
90. Spike, B. T. & Wahl, G. M. p53, stem cells, and reprogramming: tumor suppression beyond guarding the genome. Genes Cancer 2, 404-419 (2011).
91. Donehower, L. A. & Lozano, G. 20 years studying p53 functions in genetically engineered mice. Nat. Rev. Cancer 9, 831-841 (2009).
92. Jones, S. N., Roe, A. E., Donehower, L. A. & Bradley, A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378, 206-208 (1995).
93. Montes de Oca, L. R., Wagner, D. S. & Lozano, G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203-206 (1995).
94. Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083-1095 (2009).
95. Lin, T. et al. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat. Cell Biol. 7, 165-171 (2005). (Pubitemid 40268131)
96. Pereira, L., Yi, F. & Merrill, B. J. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Mol. Cell Biol. 26, 7479-7491 (2006). (Pubitemid 44547699)
97. Ruiz, S. et al. A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity. Curr. Biol. 21, 45-52 (2011).
98. Li, H. et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136-1139 (2009).
99. Hong, H. et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460, 1132-1135 (2009).
100. Kawamura, T. et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460, 1140-1144 (2009).
101. Qin, H. et al. Regulation of apoptosis and differentiation by p53 in human embryonic stem cells. J. Biol. Chem. 282, 5842-5852 (2007). (Pubitemid 47093795)
102. Yang, Y. L. et al. Amplification of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell carcinoma. Genes Chromosome Canc. 47, 127-136 (2008).
103. Blum, B. & Benvenisty, N. The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8, 3822-3830 (2009).
104. Mizuno, H., Spike, B. T., Wahl, G. M. & Levine, A. J. Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures. Proc. Natl. Acad. Sci. USA 107, 22745-22750 (2010).
105. Jiang, Z. et al. RB1 and p53 at the crossroad of EMT and triple-negative breast cancer. Cell Cycle 10, 1563-1570 (2011).
106. Kogan-Sakin, I. et al. Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells. Cell Death. Differ. 18, 271-281 (2011).
107. Wang, S. P. et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat. Cell Biol. 11, 694-704 (2009).
108. Senoo, M., Pinto, F., Crum, C. P. & McKeon, F. p63 is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129, 523-536 (2007). (Pubitemid 46660965)
109. Chang, C. J. et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol. 13, 317-323 (2011).
110. He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130-1134 (2007). (Pubitemid 47014436)
111. Hermeking, H. The miR-34 family in cancer and apoptosis. Cell Death. Differ. 17, 193-199 (2010).
112. Kim, T. et al. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J. Exp. Med. 208, 875-883 (2011).
113. Brabletz, S. & Brabletz, T. The ZEB/miR-200 feedback loop-a motor of cellular plasticity in development and cancer? EMBO Rep. 11, 670-677 (2010).
114. Bracken, C. P. et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68, 7846-7854 (2008).
115. Burk, U. et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9, 582-589 (2008). (Pubitemid 351772923)
116. Siemens, H. et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 10, 4256-4271 (2011).
117. Shi, L. et al. p53-induced miR-15a/16-11 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer. Cancer Res. 74, 532-542 (2014).
118. Isenmann, S. et al. TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment. Stem Cells 27, 2457-2468 (2009).
119. Chng, Z., Teo, A., Pedersen, R. A. & Vallier, L. SIP1 mediates cell-fate decisions between neuroectoderm and mesendoderm in human pluripotent stem cells. Cell Stem Cell 6, 59-70 (2010).
120. Goossens, S. et al. The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization. Blood 117, 5620-5630 (2011).
121. Proia, T. A. et al. Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem Cell 8, 149-163 (2011).
122. Caramel, J. et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24, 466-480 (2013).
123. Hoek, K. S. & Goding, C. R. Cancer stem cells versus phenotype-switching in melanoma. Pigm. Cell Melanoma Res. 23, 746-759 (2010).
124. Quintana, E. et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18, 510-523 (2010).
125. Shirley, S. H. et al. Slug expression during melanoma progression. Am. J. Pathol. 180, 2479-2489 (2012).
126. Sanchez-Martin, M. et al. SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum. Mol. Genet. 11, 3231-3236 (2002). (Pubitemid 35439434)
127. Sanchez-Martin, M. et al. Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am. J. Med. Genet. A 122A, 125-132 (2003). (Pubitemid 37122281)
128. Steingrimsson, E., Copeland, N. G. & Jenkins, N. A. Melanocytes and the microphthalmia transcription factor network. Annu. Rev. Genet. 38, 365-411 (2004). (Pubitemid 40013733)
129. Van de Putte, T. et al. Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease-mental retardation syndrome. Am. J. Hum. Genet. 72, 465-470 (2003).
130. Dastot-Le, M. F. et al. ZFHX1B mutations in patients with Mowat-Wilson syndrome. Hum. Mutat. 28, 313-321 (2007).
131. Wakamatsu, N. et al. Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat. Genet. 27, 369-370 (2001). (Pubitemid 32268414)
132. Karreth, F. A. et al. In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382-395 (2011).
133. Mejlvang, J. et al. Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial mesenchymal transition. Mol. Biol. Cell 18, 4615-4624 (2007). (Pubitemid 350060186)
134. Ozturk, N. et al. Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells. Proc. Natl. Acad. Sci. USA 103, 2178-2183 (2006). (Pubitemid 43271643)
135. Liu, Y. et al. Zeb1 represses Mitf and regulates pigment synthesis, cell proliferation, and epithelial morphology. Invest Ophthalmol. Vis. Sci. 50, 5080-5088 (2009).
136. Gupta, P. B. et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nat. Genet. 37, 1047-1054 (2005). (Pubitemid 41486656)
137. Klein, C. A. Cancer. The metastasis cascade. Science 321, 1785-1787 (2008).