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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2015

01-02-2015 | Preclinical study

Prognostic significance of epithelial–mesenchymal transition proteins Twist and Foxc2 in phyllodes tumours of the breast

Authors: Jeffrey Chun Tatt Lim, Valerie Cui Yun Koh, Jane Sie Yong Tan, Wai Jin Tan, Aye Aye Thike, Puay Hoon Tan

Published in: Breast Cancer Research and Treatment | Issue 1/2015

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Abstract

Epithelial–mesenchymal transition (EMT), an important process during embryonic development, is reportedly exploited during tumour progression. Deregulation of EMT-related molecules has been shown in many malignancies, including breast carcinoma. We aim to investigate the clinical relevance and prognostic significance of EMT proteins, Twist and Foxc2, in breast phyllodes tumours (PTs). The study cohort comprised 271 PTs diagnosed from 2003 to 2010. Of these, 188 (69.4 %) were benign, 60 (22.1 %) borderline, and 23 (8.5 %) malignant. Immunohistochemistry for Twist and Foxc2 was performed on tissue microarray sections. Percentage of tumour cells stained was evaluated and correlated with clinicopathological parameters and clinical outcome. Twist and Foxc2 stromal nuclear expression was associated with tumour grade (P = 0.038 and 0.012). Foxc2 stromal nuclear expression was positively correlated with epithelial expression (P < 0.001), tumour relapse, and metastasis (P = 0.037). Furthermore, stromal nuclear immunoreactivity of Twist and Foxc2 was interrelated (P < 0.001). Tumours expressing Foxc2 and those co-expressing both Twist and Foxc2 revealed a shorter time to recurrence (P < 0.001 and 0.001) and death (P = 0.044 and 0.015). Twist and Foxc2 stromal expression in PTs was significantly correlated with tumour grade and worse histological features. In addition, expression of Foxc2 and co-expression of Twist and Foxc2 in the stroma of PTs contributed to poorer prognosis. Clinical relevance of EMT-related molecules may be worthy of further investigation in PTs.
Literature
1.
Tan PH, Jayabaskar T, Chuah KL, Lee HY, Tan Y, Hilmy M, Hung H, Selvarajan S, Bay BH (2005) Phyllodes tumors of the breast: the role of pathologic parameters. Am J Clin Pathol 123:529–540CrossRefPubMed
2.
Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ (2012) Who classification of tumours of the breast, 4th edn. International Agency for Research on Cancer, Lyon
3.
Noguchi S, Motomura K, Inaji H, Imaoka S, Koyama H (1993) Clonal analysis of fibroadenoma and phyllodes tumor of the breast. Cancer Res 53:4071–4074PubMed
4.
Karim RZ, O’Toole SA, Scolyer RA, Cooper CL, Chan B, Selinger C, Yu B, Carmalt H, Mak C, Tse GM, Tan PH, Putti TC, Lee CS (2013) Recent insights into the molecular pathogenesis of mammary phyllodes tumours. J Clin Pathol 66:496–505CrossRefPubMed
5.
Sawyer EJ, Hanby AM, Rowan AJ, Gillett CE, Thomas RE, Poulsom R, Lakhani SR, Ellis IO, Ellis P, Tomlinson IPM (2002) The Wnt pathway, epithelial–stromal interactions, and malignant progression in phyllodes tumours. J Pathol 196:437–444CrossRefPubMed
6.
Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454CrossRefPubMed
7.
8.
9.
Moustakas A, Heldin CH (2007) Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 98:1512–1520CrossRefPubMed
10.
Lee TK, Poon RTP, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST (2006) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial–mesenchymal transition. Clin Cancer Res 12:5369–5376CrossRefPubMed
11.
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 103:18969–18974CrossRefPubMedCentralPubMed
12.
Zhu JL, Song YX, Wang ZN, Gao P, Wang MX, Dong YL, Xing CZ, Xu HM (2013) The clinical significance of mesenchyme forkhead 1 (foxc2) in gastric carcinoma. Histopathology 62:1038–1048CrossRefPubMed
13.
Thisse B, el Messal M, Perrin-Schmitt F (1987) The twist gene: isolation of a drosophila zygotic gene necessary for the establishment of dorsoventral pattern. Nucleic Acids Res 15:3439–3453CrossRefPubMedCentralPubMed
14.
15.
Castanon I, Baylies MK (2002) A twist in fate: evolutionary comparison of twist structure and function. Gene 287:11–22CrossRefPubMed
16.
Bastid J, Ciancia C, Puisieux A, Ansieau S (2010) Role of twist proteins in cancer progression. Atlas Genet Cytogenet Oncol Haematol 14:898–907
17.
Watanabe O, Imamura H, Shimizu T, Kinoshita J, Okabe T, Hirano A, Yoshimatsu K, Konno S, Aiba M, Ogawa K (2004) Expression of twist and Wnt in human breast cancer. Anticancer Res 24:3851–3856PubMed
18.
Gort EH, Suijkerbuijk KPM, Roothaan SM, Raman V, Vooijs M, van der Wall E, van Diest PJ (2008) Methylation of the Twist1 promoter, Twist1 mrna levels, and immunohistochemical expression of Twist1 in breast cancer. Cancer Epidemiol Biomarkers Prev 17:3325–3330CrossRefPubMed
19.
20.
Gao XH, Yang XQ, Wang BC, Liu SP, Wang FB (2013) Overexpression of twist and matrix metalloproteinase-9 with metastasis and prognosis in gastric cancer. Asian Pac J Cancer Prev 14:5055–5060CrossRefPubMed
21.
Ohuchida K, Mizumoto K, Ohhashi S, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M (2007) Twist, a novel oncogene, is upregulated in pancreatic cancer: clinical implication of twist expression in pancreatic juice. Int J Cancer 120:1634–1640CrossRefPubMed
22.
Shen CH, Wu JD, Jou YC, Cheng MC, Lin CT, Chen PC, Tseng YS, Shi CS, Chen SY, Chang DC, Lee YR (2011) The correlation between twist, e-cadherin, and beta-catenin in human bladder cancer. J BUON 16:733–737PubMed
23.
Kwok WK, Ling MT, Lee TW, Lau TCM, Zhou C, Zhang X, Chua CW, Chan KW, Chan FL, Glackin C, Wong YC, Wang X (2005) Up-regulation of twist in prostate cancer and its implication as a therapeutic target. Cancer Res 65:5153–5162CrossRefPubMed
24.
Hosono S, Kajiyama H, Terauchi M, Shibata K, Ino K, Nawa A, Kikkawa F (2007) Expression of twist increases the risk for recurrence and for poor survival in epithelial ovarian carcinoma patients. Br J Cancer 96:314–320CrossRefPubMedCentralPubMed
25.
Entz-Werlé N, Stoetzel C, Berard-Marec P, Kalifa C, Brugiere L, Pacquement H, Schmitt C, Tabone MD, Gentet JC, Quillet R, Oudet P, Lutz P, Babin-Boilletot A, Gaub MP, Perrin-Schmitt F (2005) Frequent genomic abnormalities at twist in human pediatric osteosarcomas. Int J Cancer 117:349–355CrossRefPubMed
26.
Yin K, Liao Q, He H, Zhong D (2012) Prognostic value of twist and e-cadherin in patients with osteosarcoma. Med Oncol 29:3449–3455CrossRefPubMed
27.
Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH, Hannon GJ (1999) Twist is a potential oncogene that inhibits apoptosis. Genes Dev 13:2207–2217CrossRefPubMedCentralPubMed
28.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939CrossRefPubMed
29.
Martin TA, Goyal A, Watkins G, Jiang WG (2005) Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 12:488–496CrossRefPubMed
30.
Lam EWF, Brosens JJ, Gomes AR, Koo CY (2013) Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer 13:482–495CrossRefPubMed
31.
Miura N, Wanaka A, Tohyama M, Tanaka K (1993) Mfh-1, a new member of the fork head domain family, is expressed in developing mesenchyme. FEBS Lett 326:171–176CrossRefPubMed
32.
Carlsson P, Mahlapuu M (2002) Forkhead transcription factors: key players in development and metabolism. Dev Biol 250:1–23CrossRefPubMed
33.
Seo S, Fujita H, Nakano A, Kang M, Duarte A, Kume T (2006) The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev Biol 294:458–470CrossRefPubMed
34.
Seo S, Kume T (2006) Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract. Dev Biol 296:421–436CrossRefPubMed
35.
Cederberg A, Grønning LM, Ahrén B, Taskén K, Carlsson P, Enerbäck S (2001) Foxc2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106:563–573CrossRefPubMed
36.
Sano H, Leboeuf JP, Novitskiy SV, Seo S, Zaja-Milatovic S, Dikov MM, Kume T (2010) The Foxc2 transcription factor regulates tumor angiogenesis. Biochem Biophys Res Commun 392:201–206CrossRefPubMedCentralPubMed
37.
Yang J, Weinberg RA (2008) Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829CrossRefPubMed
38.
Sasahira T, Ueda N, Yamamoto K, Kurihara M, Matsushima S, Bhawal UK, Kirita T, Kuniyasu H (2014) Prox1 and Foxc2 act as regulators of lymphangiogenesis and angiogenesis in oral squamous cell carcinoma. PLoS ONE 9:e92534CrossRefPubMedCentralPubMed
39.
Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA (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 104:10069–10074CrossRefPubMedCentralPubMed
40.
Jiang W, Pang XG, Wang Q, Shen YX, Chen XK, Xi JJ (2012) Prognostic role of twist, slug, and Foxc2 expression in stage i non-small-cell lung cancer after curative resection. Clin Lung Cancer 13:280–287CrossRefPubMed
41.
Nishida N, Mimori K, Yokobori T, Sudo T, Tanaka F, Shibata K, Ishii H, Doki Y, Mori M (2011) Foxc2 is a novel prognostic factor in human esophageal squamous cell carcinoma. Ann Surg Oncol 18:535–542CrossRefPubMed
42.
Li Y, Yang W, Yang Q, Zhou S (2012) Nuclear localization of Gli1 and elevated expression of Foxc2 in breast cancer is associated with the basal-like phenotype. Histol Histopathol 27:475–484PubMed
43.
Do SI, Kim JY, Kang SY, Lee JJ, Lee JE, Nam SJ, Cho EY (2013) Expression of twist1, snail, slug, and nf-κb and methylation of the twist1 promoter in mammary phyllodes tumor. Tumour Biol 34:445–453CrossRefPubMed
44.
Kwon JE, Jung WH, Koo JS (2012) Molecules involved in epithelial–mesenchymal transition and epithelial–stromal interaction in phyllodes tumors: implications for histologic grade and prognosis. Tumour Biol 33:787–798CrossRefPubMed
45.
van Nes JGH, de Kruijf EM, Putter H, Faratian D, Munro A, Campbell F, Smit VTHBM, Liefers GJ, Kuppen PJK, van de Velde CJH, Bartlett JMS (2012) Co-expression of snail and twist determines prognosis in estrogen receptor-positive early breast cancer patients. Breast Cancer Res Treat 133:49–59CrossRefPubMed
46.
Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, Peng WL, Wu JC (2009) Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology 50:1464–1474CrossRefPubMed
47.
Tan PH, Thike AA, Tan WJ, Thu MMM, Busmanis I, Li H, Chay WY, Tan MH, Phyllodes Tumour Network Singapore (2012) Predicting clinical behaviour of breast phyllodes tumours: a nomogram based on histological criteria and surgical margins. J Clin Pathol 65:69–76CrossRefPubMed
48.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of NCI-EORTC Working Group on Cancer Diagnostics (2006) Reporting recommendations for tumor marker prognostic studies. Breast Cancer Res Treat 100:229–235CrossRefPubMed
49.
Sawyer EJ, Hanby AM, Ellis P, Lakhani SR, Ellis IO, Boyle S, Tomlinson IP (2000) Molecular analysis of phyllodes tumors reveals distinct changes in the epithelial and stromal components. Am J Pathol 156:1093–1098CrossRefPubMedCentralPubMed
50.
Dietrich CU, Pandis N, Rizou H, Petersson C, Bardi G, Qvist H, Apostolikas N, Bøhler PJ, Andersen JA, Idvall I, Mitelman F, Heim S (1997) Cytogenetic findings in phyllodes tumors of the breast: karyotypic complexity differentiates between malignant and benign tumors. Hum Pathol 28:1379–1382CrossRefPubMed
51.
Sawhney N, Garrahan N, Douglas-Jones AG, Williams ED (1992) Epithelial–stromal interactions in tumors. A morphologic study of fibroepithelial tumors of the breast. Cancer 70:2115–2120CrossRefPubMed
52.
Millar EK, Beretov J, Marr P, Sarris M, Clarke RA, Kearsley JH, Lee CS (1999) Malignant phyllodes tumours of the breast display increased stromal p53 protein expression. Histopathology 34:491–496CrossRefPubMed
53.
Tsang JYS, Mendoza P, Putti TC, Karim RZ, Scolyer RA, Lee CS, Pang ALM, Tse GM (2012) E-cadherin expression in the epithelial components of mammary phyllodes tumors. Hum Pathol 43:2117–2123CrossRefPubMed
54.
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 64:807–817CrossRefPubMed
55.
Hayashi H, Sano H, Seo S, Kume T (2008) The Foxc2 transcription factor regulates angiogenesis via induction of integrin beta3 expression. J Biol Chem 283:23791–23800CrossRefPubMedCentralPubMed
56.
Mortazavi F, An J, Dubinett S, Rettig M (2010) P120-catenin is transcriptionally downregulated by foxc2 in non-small cell lung cancer cells. Mol Cancer Res 8:762–774CrossRefPubMed
57.
Montserrat N, Gallardo A, Escuin D, Catasus L, Prat J, Gutiérrez-Avignó FJ, Peiró G, Barnadas A, Lerma E (2011) Repression of e-cadherin by snail, zeb1, and twist in invasive ductal carcinomas of the breast: a cooperative effort? Hum Pathol 42:103–110CrossRefPubMed
58.
Mironchik Y, Winnard PT, Vesuna F, Kato Y, Wildes F, Pathak AP, Kominsky S, Artemov D, Bhujwalla Z, Van Diest P, Burger H, Glackin C, Raman V (2005) Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 65:10801–10809CrossRefPubMed
59.
Vesuna F, Lisok A, Kimble B, Raman V (2009) Twist modulates breast cancer stem cells by transcriptional regulation of cd24 expression. Neoplasia 11:1318–1328PubMedCentralPubMed
60.
Hollier BG, Tinnirello AA, Werden SJ, Evans KW, Taube JH, Sarkar TR, Sphyris N, Shariati M, Kumar SV, Battula VL, Herschkowitz JI, Guerra R, Chang JT, Miura N, Rosen JM, Mani SA (2013) Foxc2 expression links epithelial–mesenchymal transition and stem cell properties in breast cancer. Cancer Res 73:1981–1992CrossRefPubMedCentralPubMed
Metadata
Title
Prognostic significance of epithelial–mesenchymal transition proteins Twist and Foxc2 in phyllodes tumours of the breast
Authors
Jeffrey Chun Tatt Lim
Valerie Cui Yun Koh
Jane Sie Yong Tan
Wai Jin Tan
Aye Aye Thike
Puay Hoon Tan
Publication date
01-02-2015
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2015
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-015-3296-4

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