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Expression of TWIST1, Snail, Slug, and NF-κB and methylation of the TWIST1 promoter in mammary phyllodes tumor

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Tumor Biology

Abstract

TWIST1, Slug, Snail, SIP1, and NF-κB are overexpressed in various tumors and associated with metastasis and poor prognosis. In this study, we examined their potential roles in phyllodes tumor (PT). The expression of TWIST1, Snail, Slug, SIP1, and NF-κB in benign (n = 103), borderline (n = 38), and malignant (n = 38) PTs was examined by immunostaining. The methylation status of the TWIST1 promoter was analyzed by methylation-specific PCR. We detected high expression levels of TWIST1 in 47.4 % of borderline/malignant PTs and 31.1 % of benign PTs, Slug in 64 % of borderline/malignant PTs and 62.1 % of benign PTs, epithelial SIP1 in 75.0 % of borderline/malignant PTs and 86.3 % of benign PTs, stromal SIP1 in 35.5 % of borderline/malignant PTs and 22.3 % of benign PTs, and NF-κB in 63.2 % of borderline/malignant PTs and 52.4 % of benign PTs. Snail expression was detected in all cases. A high expression of TWIST1 (p = 0.026) and TWIST1 promoter methylation (p = 0.000) were significantly more frequent in borderline/malignant PTs than in benign PTs. Moreover, a high expression of at least four of the five antibodies was more commonly observed in borderline/malignant PTs than in benign PTs (p = 0.026). However, no relationship was found between the expression of TWIST1 or the other proteins examined and the clinical outcome. Our results suggest that a high expression of TWIST1 and related proteins plays a pivotal role in the malignant progression of PT.

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References

  1. Bellocq JP, Margo G. Fibroepithelial tumors. In: Tavassoéli FA, Devilee P, editors. World Health Organization classification of tumors of the Breast. Lyon: IARC; 2012. p. 141–147.

    Google Scholar 

  2. Rosen PP. Fibroepithelial neoplasms. In: Weinberg RW, Donnellan K, Palumbo R, editors. Rosen's breast pathology. 3rd ed. Philadelphia: Williams & Wilkins; 2009. p. 187–229.

    Google Scholar 

  3. Tse GM, Putti TC, Kung FY, Scolyer RA, Law BK, Lau TS, et al. Increased p53 protein expression in malignant mammary phyllodes tumors. Mod Pathol. 2002;15(7):734–40.

    Article  PubMed  Google Scholar 

  4. Sawyer EJ, Poulsom R, Hunt FT, Jeffery R, Elia G, Ellis IO, et al. Malignant phyllodes tumours show stromal overexpression of c-myc and c-kit. J Pathol. 2003;200(1):59–64.

    Article  PubMed  CAS  Google Scholar 

  5. Tse GM, Lui PC, Vong JS, Lau KM, Putti TC, Karim R, et al. Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors. Breast Cancer Res Treat. 2009;114(3):441–8.

    Article  PubMed  CAS  Google Scholar 

  6. Tse GM, Lui PC, Lee CS, Kung FY, Scolyer RA, Law BK, et al. Stromal expression of vascular endothelial growth factor correlates with tumor grade and microvessel density in mammary phyllodes tumors: a multicenter study of 185 cases. Hum Pathol. 2004;35(9):1053–7.

    Article  PubMed  CAS  Google Scholar 

  7. Noguchi S, Motomura K, Inaji H, Imaoka S, Koyama H. Clonal analysis of fibroadenoma and phyllodes tumor of the breast. Cancer Res. 1993;53(17):4071–4.

    PubMed  CAS  Google Scholar 

  8. Kuijper A, Mommers EC, van der Wall E, van Diest PJ. Histopathology of fibroadenoma of the breast. Am J Clin Pathol. 2001;115(5):736–42.

    Article  PubMed  CAS  Google Scholar 

  9. Tan PH, Jayabaskar T, Chuah KL, Lee HY, Tan Y, Hilmy M, et al. Phyllodes tumors of the breast: the role of pathologic parameters. Am J Clin Pathol. 2005;123(4):529–40.

    Article  PubMed  Google Scholar 

  10. Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial–mesenchymal transition. Clin Cancer Res. 2006;12(18):5369–76.

    Article  PubMed  CAS  Google Scholar 

  11. Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, et al. Differential expression of the epithelial–mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 2002;161(5):1881–91.

    Article  PubMed  CAS  Google Scholar 

  12. Gort EH, Suijkerbuijk KP, Roothaan SM, Raman V, Vooijs M, van der Wall E, et al. Methylation of the TWIST1 promoter, TWIST1 mRNA levels, and immunohistochemical expression of TWIST1 in breast cancer. Cancer Epidemiol Biomarkers Prev. 2008;17(12):3325–30.

    Article  PubMed  CAS  Google Scholar 

  13. Yuen HF, Chan YP, Wong ML, Kwok WK, Chan KK, Lee PY, et al. Upregulation of Twist in oesophageal squamous cell carcinoma is associated with neoplastic transformation and distant metastasis. J Clin Pathol. 2007;60(5):510–4.

    Article  PubMed  CAS  Google Scholar 

  14. Ohuchida K, Mizumoto K, Ohhashi S, Yamaguchi H, Konomi H, Nagai E, et al. Twist, a novel oncogene, is upregulated in pancreatic cancer: clinical implication of Twist expression in pancreatic juice. Int J Cancer. 2007;120(8):1634–40.

    Article  PubMed  CAS  Google Scholar 

  15. Zhang Z, **e D, Li X, Wong YC, **n D, Guan XY, et al. Significance of TWIST expression and its association with E-cadherin in bladder cancer. Hum Pathol. 2007;38(4):598–606.

    Article  PubMed  CAS  Google Scholar 

  16. Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, et al. Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999;13(17):2207–17.

    Article  PubMed  CAS  Google Scholar 

  17. D'Angelo E, Spagnoli LG, Prat J. Comparative clinicopathologic and immunohistochemical analysis of uterine sarcomas diagnosed using the World Health Organization classification system. Hum Pathol. 2009;40(11):1571–85.

    Article  PubMed  Google Scholar 

  18. Entz-Werle N, Stoetzel C, Berard-Marec P, Kalifa C, Brugiere L, Pacquement H, et al. Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas. Int J Cancer. 2005;117(3):349–55.

    Article  PubMed  CAS  Google Scholar 

  19. Man TK, Chintagumpala M, Visvanathan J, Shen J, Perlaky L, Hicks J, et al. Expression profiles of osteosarcoma that can predict response to chemotherapy. Cancer Res. 2005;65(18):8142–50.

    Article  PubMed  CAS  Google Scholar 

  20. Huang KT, Dobrovic A, Yan M, Karim RZ, Lee CS, Lakhani SR, et al. DNA methylation profiling of phyllodes and fibroadenoma tumours of the breast. Breast Cancer Res Treat. 2010;124(2):555–65.

    Article  PubMed  CAS  Google Scholar 

  21. Kim JH, Choi YD, Lee JS, Lee JH, Nam JH, Choi C, et al. Borderline and malignant phyllodes tumors display similar promoter methylation profiles. Virchows Arch. 2009;455(6):469–75.

    Article  PubMed  CAS  Google Scholar 

  22. Kwon JE, Jung WH, Koo JS. Molecules involved in epithelial–mesenchymal transition and epithelial–stromal interaction in phyllodes tumors: implications for histologic grade and prognosis. Tumour Biol. 2012;33(3):787–98.

    Article  PubMed  Google Scholar 

  23. Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;62(6):1613–8.

    PubMed  CAS  Google Scholar 

  24. Yokoyama K, Kamata N, Hayashi E, Hoteiya T, Ueda N, Fujimoto R, et al. Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol. 2001;37(1):65–71.

    Article  PubMed  CAS  Google Scholar 

  25. Jiao W, Miyazaki K, Kitajima Y. Inverse correlation between E-cadherin and Snail expression in hepatocellular carcinoma cell lines in vitro and in vivo. Br J Cancer. 2002;86(1):98–101.

    Article  PubMed  CAS  Google Scholar 

  26. Maeda G, Chiba T, Okazaki M, Satoh T, Taya Y, Aoba T, et al. Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol. 2005;27(6):1535–41.

    PubMed  CAS  Google Scholar 

  27. Bindels S, Mestdagt M, Vandewalle C, Jacobs N, Volders L, Noel A, et al. Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene. 2006;25(36):4975–85.

    Article  PubMed  CAS  Google Scholar 

  28. Orlowski RZ, Baldwin Jr AS. NF-kappaB as a therapeutic target in cancer. Trends Mol Med. 2002;8(8):385–9.

    Article  PubMed  CAS  Google Scholar 

  29. Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, et al. NF-kappaB is essential for epithelial–mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114(4):569–81.

    PubMed  CAS  Google Scholar 

  30. Zhang C, Klymkowsky MW. Unexpected functional redundancy between Twist and Slug (Snail2) and their feedback regulation of NF-kappaB via Nodal and Cerberus. Dev Biol. 2009;331(2):340–9.

    Article  PubMed  CAS  Google Scholar 

  31. Kim SH, Lee SH, Choi YL, Wang LH, Park CK, Shin YK. Extensive alteration in the expression profiles of TGFB pathway signaling components and TP53 is observed along the gastric dysplasia–carcinoma sequence. Histol Histopathol. 2008;23(12):1439–52.

    PubMed  CAS  Google Scholar 

  32. Kyo S, Sakaguchi J, Ohno S, Mizumoto Y, Maida Y, Hashimoto M, et al. High Twist expression is involved in infiltrative endometrial cancer and affects patient survival. Hum Pathol. 2006;37(4):431–8.

    Article  PubMed  CAS  Google Scholar 

  33. Miura N, Yano T, Shoji F, Kawano D, Takenaka T, Ito K, et al. Clinicopathological significance of Sip1-associated epithelial mesenchymal transition in non-small cell lung cancer progression. Anticancer Res. 2009;29(10):4099–106.

    PubMed  Google Scholar 

  34. Fackler MJ, McVeigh M, Evron E, Garrett E, Mehrotra J, Polyak K, et al. DNA methylation of RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma. Int J Cancer. 2003;107(6):970–5.

    Article  PubMed  CAS  Google Scholar 

  35. Okada T, Suehiro Y, Ueno K, Mitomori S, Kaneko S, Nishioka M, et al. TWIST1 hypermethylation is observed frequently in colorectal tumors and its overexpression is associated with unfavorable outcomes in patients with colorectal cancer. Genes Chromosomes Cancer. 2010;49(5):452–62.

    PubMed  CAS  Google Scholar 

  36. Martin TA, Goyal A, Watkins G, Jiang WG. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol. 2005;12(6):488–96.

    Article  PubMed  Google Scholar 

  37. Yuen HF, Chua CW, Chan YP, Wong YC, Wang X, Chan KW. Significance of TWIST and E-cadherin expression in the metastatic progression of prostatic cancer. Histopathology. 2007;50(5):648–58.

    Article  PubMed  Google Scholar 

  38. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial–mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17(5):548–58.

    Article  PubMed  CAS  Google Scholar 

  39. Papageorgis P, Lambert AW, Ozturk S, Gao F, Pan H, Manne U, et al. Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res. 2010;70(3):968–78.

    Article  PubMed  CAS  Google Scholar 

  40. Korchynskyi O, Landstrom M, Stoika R, Funa K, Heldin CH, ten Dijke P, et al. Expression of Smad proteins in human colorectal cancer. Int J Cancer. 1999;82(2):197–202.

    Article  PubMed  CAS  Google Scholar 

  41. Elloul S, Elstrand MB, Nesland JM, Trope CG, Kvalheim G, Goldberg I, et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer. 2005;103(8):1631–43.

    Article  PubMed  CAS  Google Scholar 

  42. van Nes JG, de Kruijf EM, Putter H, Faratian D, Munro A, Campbell F, et al. Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients. Breast Cancer Res Treat. 2012;133(1):49–59.

    Article  PubMed  CAS  Google Scholar 

  43. Ling ZQ, Li P, Ge MH, Zhao X, Hu FJ, Fang XH, et al. Hypermethylation-modulated down-regulation of CDH1 expression contributes to the progression of esophageal cancer. Int J Mol Med. 2011;27(5):625–35.

    Article  PubMed  CAS  Google Scholar 

  44. Yi B, Tan SX, Tang CE, Huang WG, Cheng AL, Li C, et al. Inactivation of 14-3-3 sigma by promoter methylation correlates with metastasis in nasopharyngeal carcinoma. J Cell Biochem. 2009;106(5):858–66.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by the Samsung Biomedical Research Institute grant (#SBRI C-B0-319-2).

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Authors and Affiliations

  1. Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

    Sung-Im Do

  2. Department of Pathology, Haeundae Paik Hospital, Inje University School of Medicine, Busan, Korea

    Ji Yeon Kim

  3. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, Korea

    So Young Kang, Jae Joon Lee & Eun Yoon Cho

  4. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, Korea

    Jeong Eon Lee & Seok ** Nam

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  1. Sung-Im Do
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Correspondence to Eun Yoon Cho.

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Sung-Im Do and Ji Yeon Kim contributed equally to this work.

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Do, SI., Kim, J.Y., Kang, S.Y. et al. Expression of TWIST1, Snail, Slug, and NF-κB and methylation of the TWIST1 promoter in mammary phyllodes tumor. Tumor Biol. 34, 445–453 (2013). https://doi.org/10.1007/s13277-012-0569-y

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