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BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Transcription factors zeb1, twist and snai1 in breast carcinoma

Published in: BMC Cancer | Issue 1/2011

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Abstract

Background

Epitheliomesenchymal transition (EMT) is the process where cancer cells attain fibroblastic features and are thus able to invade neighboring tissues. Transcriptional factors zeb1, snai1 and twist regulate EMT.

Methods

We used immunohistochemistry to investigate the expression of zeb1, twist and snai1 in tumor and stromal compartments by in a large set of breast carcinomas. The results were compared with estrogen and progesterone receptor status, HER2 amplification, grade, histology, TNM status and survival of the patients.

Results

Nuclear expression for twist was seen in the epithelial tumor cell compartment in 3.6% and for snai1 in 3.1% of the cases while zeb1 was not detected at all in these areas. In contrast, the tumor stromal compartment showed nuclear zeb1 and twist expression in 75% and 52.4% of the cases, respectively. Although rare, nuclear expression of twist in the epithelial tumor cell compartment was associated with a poor outcome of the patients (p = 0.054 log rank, p = 0.013, Breslow, p = 0.025 Tarone-Ware). Expression of snai1, or expression of zeb1 or twist in the stromal compartment did not have any prognostic significance. Furthermore, none of these factors associated with the size of the tumors, nor with the presence of axillary or distant metastases. Expression of zeb1 and twist in the stromal compartment was positively associated with a positive estrogen or progesterone receptor status of the tumors. Stromal zeb1 expression was significantly lower in ductal in situ carcinomas than in invasive carcinomas (p = 0.020). Medullary carcinomas (p = 0.017) and mucinous carcinomas (p = 0.009) had a lower stromal expression of zeb1 than ductal carcinomas. Stromal twist expression was also lower in mucinous (p = 0.017) than in ductal carcinomas.

Conclusions

Expression of transcriptional factors zeb1 and twist mainly occur in the stromal compartment of breast carcinomas, possibly representing two populations of cells; EMT transformed neoplastic cells and stromal fibroblastic cells undergoing activation of zeb1 and twist due to growth factors produced by the tumor. However, epithelial expression of twist was associated with a poor prognosis, hinting at its importance in the spread of breast carcinoma.
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Literature
1.
Schmalhofer O, Brabletz S, Brabletz T: E-cadherin, beta-catenin, and zeb1 in malignant progression of cancer. Cancer Metastasis Rev. 2009, 28: 151-66. 10.1007/s10555-008-9179-y.CrossRefPubMed
2.
De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, Redeuilh G, Gespach C, Bracke M, Berx G: Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol. 2008, 130: 481-494. 10.1007/s00418-008-0464-1.CrossRefPubMedPubMedCentral
3.
Peinado H, Olmeda D, Cano A: Snail, ZEB and bHLH factors in tumour progression; and alliance against the epithelial phenotype. Nature Rev Cancer. 2007, 7: 415-428. 10.1038/nrc2131.CrossRef
4.
Hurt EM, Saykally JN, Anose BM, Kalli KR, Sanders MM: Expression of the zeb1 (deltaEF1) transcription factor in human: additional insights. Mol Cell Biochem. 2008, 318: 89-99. 10.1007/s11010-008-9860-z.CrossRefPubMed
5.
Singh M, Spoelstra NS, Jean A, Howe E, Torkko KC, Clark HR, Darling DS, Shroyer KR, Horwitz KB, Broaddus RR, Richer JK: zeb1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol. 2008, 21: 912-23. 10.1038/modpathol.2008.82.CrossRefPubMed
6.
Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A, Hlubek F, Jung A, Strand D, Eger A, Kirchner T, Behrens J, Brabletz T: The transcriptional repressor zeb1 promotes metastasis and loss of cell polarity in cancer. Cancer Res. 2008, 68: 537-44. 10.1158/0008-5472.CAN-07-5682.CrossRefPubMed
7.
Vandewalle C, Van Roy F, Berx G: The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci. 2009, 66: 773-87. 10.1007/s00018-008-8465-8.CrossRefPubMed
8.
Katoh Y, Katoh M: Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med. 2009, 9: 873-86. 10.2174/156652409789105570.CrossRefPubMed
9.
Korpal M, Lee ES, Hu G, Kang Y: The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors zeb1 and ZEB2. J Biol Chem. 2008, 283: 14910-4. 10.1074/jbc.C800074200.CrossRefPubMedPubMedCentral
10.
Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST: Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2006, 12: 5369-76. 10.1158/1078-0432.CCR-05-2722.CrossRefPubMed
11.
Pena W, Slavotinek A, Oberoi S: Saethre-Chotzen Syndrome: A Case Report. Cleft Palate Craniofac J. 2009
12.
Matsuo N, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Tanaka S, Nishina S, Nakanishi Y, Uemura M, Takaki A, Nakamura S, Kobayashi Y, Nouso K, Yagi T, Yamamoto K: Twist expression promotes migration and invasion in hepatocellular carcinoma. BMC Cancer. 2009, 9: 240-10.1186/1471-2407-9-240.CrossRefPubMedPubMedCentral
13.
Kwok WK, Ling MT, Lee TW, Lau TC, Zhou C, Zhang X, Chua CW, Chan KW, Chan FL, Glackin C, Wong YC, Wang X: Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res. 2005, 65: 5153-62. 10.1158/0008-5472.CAN-04-3785.CrossRefPubMed
14.
Blechschmidt K, Sassen S, Schmalfeldt B, Schuster T, Höffler H, Becker KF: The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients. Br J Cancer. 2008, 98: 489-95. 10.1038/sj.bjc.6604115.CrossRefPubMed
15.
Hipp S, Walch A, Schuster T, Höffler H, Becker KF: Precise measurement of the E-cadherin repressor Snail in formalin-fixed endometrial carcinoma using protein lysate microarrays. Clin Exp Metastasis. 2008, 25: 679-83. 10.1007/s10585-008-9149-3.CrossRefPubMed
16.
Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, Dargemont C, de Herreros AG, Bellacosa A, Larue L: Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene. 2007, 26: 7445-56. 10.1038/sj.onc.1210546.CrossRefPubMed
17.
Olmeda D, Montes A, Moreno-Bueno G, Flores JM, Portillo F, Cano A: Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines. Oncogene. 2008, 27: 4690-4701. 10.1038/onc.2008.118.CrossRefPubMed
18.
Yang MH, Chang SY, Chiou SH, Liu CJ, Chi CW, Chen PM, Teng SC, Wu KJ: Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene. 2007, 26: 1459-67. 10.1038/sj.onc.1209929.CrossRefPubMed
19.
Barrallo-Gimeno A, Nieto MA: The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005, 132: 3151-61. 10.1242/dev.01907.CrossRefPubMed
20.
Olmeda D, Jordan M, Peinado H, Fabra A, Cano A: Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene. 2007, 26: 1862-74. 10.1038/sj.onc.1209997.CrossRefPubMed
21.
Tavassoli FA, Devilee P: Tumours of the breast and Female genital Organs. World Health Organization Classification of Tumours. 2003, IARC press, Lyon, France
22.
Hartikainen JM, Tuhkanen H, Kataja V, Dunning AM, Antoniou A, Smith P, Arffman A, Pirskanen M, Easton DF, Eskelinen M, Uusitupa M, Kosma VM, Mannermaa A: An Autosome-Wide Scan for Linkage Disequilibrium-Based Association in Sporadic Breast Cancer Cases in Eastern Finland: Three Candidate Regions Found. Cancer Epidemiol Biomarkers Prev. 2005, 14: 75-80.PubMed
23.
Franci C, Takkunen M, Dave N, Alameda F, Gomez S, Rodriguez R, et al: Expression of Snail protein in tumor-stroma interface. Oncogene. 2006, 25: 5134-5144.PubMed
24.
Takkunen M, Grenman R, Hukkanen M, Korhonen M, Garcia de Herreros A, Virtanen I: Snail-dependent and -independent epithelial-mesenchymal transition in oral squamous carcinoma cells. J Histochem Cytochem. 2006, 54: 1263-1275. 10.1369/jhc.6A6958.2006.CrossRefPubMed
25.
Cates JM, Byrd RH, Fohn LE, Tatsas AD, Washington MK, Black CC: Epithelial-mesenchymal transition markers in pancreatic ductal adenocarcinoma. Pancreas. 2009, 38: e1-6. 10.1097/MPA.0b013e3181878b7f.CrossRefPubMedPubMedCentral
26.
27.
Radisky DC, Kenny PA, Bissell MJ: Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT?. J Cell Biochem. 2007, 101: 830-839. 10.1002/jcb.21186.CrossRefPubMedPubMedCentral
28.
Thiery JP, Acloque H, Huang RYJ, Nieto MA: Epithelio-mesenchymal transitions in development and disease. Cell. 2009, 139: 871-890. 10.1016/j.cell.2009.11.007.CrossRefPubMed
29.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004, 117: 927-39. 10.1016/j.cell.2004.06.006.CrossRefPubMed
30.
Okamura H, Yoshida K, Haneji T: Negative regulation of TIMP1 is mediated by transcription factor TWIST1. Int J Oncol. 2009, 35: 181-6.PubMed
31.
Niu RF, Zhang L, Xi GM, Wei XY, Yang Y, Shi YR, Hao XS: Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2007, 26: 385-94.PubMed
32.
Yang AD, Camp ER, Fan F, Shen L, Gray MJ, Liu W, Somcio R, Bauer TW, Wu Y, Hicklin DJ, Ellis LM: Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 2006, 66: 46-51. 10.1158/0008-5472.CAN-05-3086.CrossRefPubMed
33.
Li QQ, Xu JD, Wang WJ, Cao XX, Chen Q, Tang F, Chen ZQ, Liu XP, Xu ZD: Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res. 2009, 15: 2657-65. 10.1158/1078-0432.CCR-08-2372.CrossRefPubMed
34.
Shibata K, Kajiyama H, Ino K, Terauchi M, Yamamoto E, Nawa A, Nomura S, Kikkawa F: Twist expression in patients with cervical cancer is associated with poor disease outcome. Ann Oncol. 2008, 19: 81-5. 10.1093/annonc/mdm344.CrossRefPubMed
35.
Sasaki K, Natsugoe S, Ishigami S, Matsumoto M, Okumura H, Setoyama T, Uchikado Y, Kita Y, Tamotsu K, Sakamoto A, Owaki T, Aikou T: Significance of Twist expression and its association with E-cadherin in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2009, 28: 158-10.1186/1756-9966-28-158.CrossRefPubMedPubMedCentral
36.
Yan-Qi Z, Xue-Yan G, Shuang H, Yu C, Fu-Lin G, Fei-Hu B, Shi-Ren S, Xu-Feng W, Jie D, Dai-Ming F: Expression and significance of TWIST basic helix-loop-helix protein over-expression in gastric cancer. Pathology. 2007, 39: 470-5. 10.1080/00313020701570053.CrossRefPubMed
37.
Tuhkanen H, Soini Y, Kosma VM, Anttila M, Sironen R, Hämäläinen K, Kukkonen L, Virtanen I, Mannermaa A: Nuclear expression of Snail1 in borderline and malignant epithelial ovarian tumours is associated with tumour progression. BMC Cancer. 2009, 9: 289-10.1186/1471-2407-9-289.CrossRefPubMedPubMedCentral
38.
Spoelstra NS, Manning NG, Higashi Y, Darling D, Singh M, Shroyer KR, Broaddus RR, Horwitz KB, Richer JK: The transcription factor zeb1 is aberrantly expressed in aggressive uterine cancers. Cancer Res. 2006, 66: 3893-902. 10.1158/0008-5472.CAN-05-2881.CrossRefPubMed
39.
Liu Y, El-Naggar S, Darling DS, Higashi Y, Dean DC: Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development. 2008, 135: 579-588. 10.1242/dev.007047.CrossRefPubMedPubMedCentral
40.
Drafta D, Prişcu A, Neacşu E, Gangură M, Schindler AE, Stroe E, Anghel C, Panaitescu G: Estradiol and progesterone receptor levels in human breast cancer in relation to cytosol and plasma estrogen level. J Steroid Biochem. 1983, 18: 459-63. 10.1016/0022-4731(83)90066-3.CrossRefPubMed
Metadata
Title
Transcription factors zeb1, twist and snai1 in breast carcinoma
Publication date
01-12-2011
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-73

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