Prognostic significance of expression of epithelial‑mesenchymal transition driver brachyury in breast cancer and its association with subtype and characteristics

Lee,Kwan Ho; Kim,Eun Young; Yun,Ji Sup; Park,Yong Lai; Do,Sung‑Im; Chae,Seoung Wan; Park,Chan Heun

doi:10.3892/ol.2017.7402

Prognostic significance of expression of epithelial‑mesenchymal transition driver brachyury in breast cancer and its association with subtype and characteristics

Authors:
- Kwan Ho Lee
- Eun Young Kim
- Ji Sup Yun
- Yong Lai Park
- Sung‑Im Do
- Seoung Wan Chae
- Chan Heun Park
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Affiliations: Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea, Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
Published online on: November 14, 2017 https://doi.org/10.3892/ol.2017.7402
Pages: 1037-1045
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Brachyury is a T‑box transcription factor characterized as a driver of the epithelial‑to‑mesenchymal process, which is associated with poor prognosis of patients with breast cancer. The present study investigated expression of brachyury in breast cancer including primary tumor, metastatic and recurred tumor tissues, and the clinical significance and value of brachyury as a prognostic biomarker. This retrospective study included a series of 102 consecutive patients surgically resected between January 2005 and December 2011. Brachyury expression in tumor cell was evaluated using immunohistochemistry and scored as the immunoactivity. Of 102 patients, 62 primary tumors were positive for brachyury expression and 40 were negative. Multivariate analysis of disease‑free survival (DFS) revealed brachyury expression, HER2 and lymphovascular invasion as independent prognostic factors [brachyury negative vs. positive hazard ratio (HR), 3.0; P=0.024; HER2 negative vs. positive HR, 4.9; P=0.003; lymphovascular invasion absent vs. present HR, 3.5; P=0.020]. These results were particularly observed in triple‑negative breast cancer (TNBC), no recurrence or mortality occurred in brachyury negative group during the follow‑up period, and therefore a significantly improved prognosis was demonstrated in these patients compared with the brachyury positive group [overall survival (OS), P=0.022; DFS, P=0.002]. Brachyury expression in metastatic lymph node/recurred tumors was not significantly associated with prognosis (OS, P=0.745; DFS, P=0.189). Therefore, Brachyury expression in primary tumor independently is a potential predictor of poor prognosis, particularly in TNBC, where it appears to serve a crucial function in recurrence and mortality. Brachyury vaccines under clinical trials are likely to be useful in patients with breast cancer.

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1	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
2	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
3	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
4	Polyak K and Weinberg RA: Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer. 9:265–273. 2009. View Article : Google Scholar : PubMed/NCBI
5	Singh A and Settleman J: EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene. 29:4741–4751. 2010. View Article : Google Scholar : PubMed/NCBI
6	Larocca C, Cohen JR, Fernando RI, Huang B, Hamilton DH and Palena C: An autocrine loop between TGF-β1 and the transcription factor brachyury controls the transition of human carcinoma cells into a mesenchymal phenotype. Mol Cancer Ther. 12:1805–1815. 2013. View Article : Google Scholar : PubMed/NCBI
7	Fernando RI, Litzinger M, Trono P, Hamilton DH, Schlom J and Palena C: The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells. J Clin Invest. 120:533–544. 2010. View Article : Google Scholar : PubMed/NCBI
8	Rowley M, Grothey E and Couch FJ: The role of Tbx2 and Tbx3 in mammary development and tumorigenesis. J Mammary Gland Biol Neoplasia. 9:109–118. 2004. View Article : Google Scholar : PubMed/NCBI
9	Sinclair CS, Adem C, Naderi A, Soderberg CL, Johnson M, Wu K, Wadum L, Couch VL, Sellers TA, Schaid D, et al: TBX2 is preferentially amplified in BRCA1- and BRCA2-related breast tumors. Cancer Res. 62:3587–3591. 2002.PubMed/NCBI
10	Wang B, Lindley LE, Fernandez-Vega V, Rieger ME, Sims AH and Briegel KJ: The T box transcription factor TBX2 promotes epithelial-mesenchymal transition and invasion of normal and malignant breast epithelial cells. PLoS One. 7:e413552012. View Article : Google Scholar : PubMed/NCBI
11	Rodriguez M, Aladowicz E, Lanfrancone L and Goding CR: Tbx3 represses E-cadherin expression and enhances melanoma invasiveness. Cancer Res. 68:7872–7881. 2008. View Article : Google Scholar : PubMed/NCBI
12	Huang B, Cohen JR, Fernando RI, Hamilton DH, Litzinger MT, Hodge JW and Palena C: The embryonic transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to conventional antitumor therapies. Cell Death Dis. 4:e6822013. View Article : Google Scholar : PubMed/NCBI
13	Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, et al: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 295:2492–2502. 2006. View Article : Google Scholar : PubMed/NCBI
14	Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P and Narod SA: Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res. 13:4429–4434. 2007. View Article : Google Scholar : PubMed/NCBI
15	Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W and Toppmeyer D: Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 24:5652–5657. 2006. View Article : Google Scholar : PubMed/NCBI
16	Jeong H, Ryu YJ, An J, Lee Y and Kim A: Epithelial-mesenchymal transition in breast cancer correlates with high histological grade and triple-negative phenotype. Histopathology. 60:E87–E95. 2012. View Article : Google Scholar : PubMed/NCBI
17	Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G and Palacios J: Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68:989–997. 2008. View Article : Google Scholar : PubMed/NCBI
18	Palena C, Roselli M, Litzinger MT, Ferroni P, Costarelli L, Spila A, Cavaliere F, Huang B, Fernando RI, Hamilton DH, et al: Overexpression of the EMT driver brachyury in breast carcinomas: Association with poor prognosis. J Natl Cancer Inst. 106:dju0542014. View Article : Google Scholar : PubMed/NCBI
19	Hamilton DH, Roselli M, Ferroni P, Costarelli L, Cavaliere F, Taffuri M, Palena C and Guadagni F: Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer. Endocr Relat Cancer. 23:783–796. 2016. View Article : Google Scholar : PubMed/NCBI
20	Heery CR, Singh BH, Rauckhorst M, Marte JL, Donahue RN, Grenga I, Rodell TC, Dahut W, Arlen PM, Madan RA, et al: Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) targeting the transcription factor brachyury. Cancer Immunol Res. 3:1248–1256. 2015. View Article : Google Scholar : PubMed/NCBI
21	Edge SB and Compton CC: American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
22	Shimamatsu S, Okamoto T, Haro A, Kitahara H, Kohno M, Morodomi Y, Tagawa T, Okano S, Oda Y and Maehara Y: Prognostic significance of expression of the epithelial-mesenchymal transition-related factor brachyury in intrathoracic lymphatic spread of non-small cell lung cancer. Ann Surg Oncol. 23 Suppl 5:S1012–S1020. 2016. View Article : Google Scholar
23	R Development Core Team, . R: A Language and Environment for Statistical Computing. The R Foundation for Statistical Computing; Vienna: 2011, http://www.r-project.org/
24	Therneau TM: Survival: Survival Analysis. R package version 2.38. 2015, https://CRAN.R-project.org/package=survival
25	Therneau TM and Grambsch PM: Modeling survival data: Extending the Cox model. Springer; New York, NY: 2010
26	Kono M, Fujii T, Lim B, Karuturi MS, Tripathy D and Ueno NT: Androgen receptor function and androgen receptor-targeted therapies in breast cancer: A Review. JAMA Oncol. 3:1266–1273. 2017. View Article : Google Scholar : PubMed/NCBI
27	Kirsch T: Determinants of pathological mineralization. Curr Opin Rheumatol. 18:174–180. 2006. View Article : Google Scholar : PubMed/NCBI
28	Cox RF, Jenkinson A, Pohl K, O'Brien FJ and Morgan MP: Osteomimicry of mammary adenocarcinoma cells in vitro; increased expression of bone matrix proteins and proliferation within a 3D collagen environment. PLoS One. 7:e416792012. View Article : Google Scholar : PubMed/NCBI
29	Soltanoff CS, Yang S, Chen W and Li YP: Signaling networks that control the lineage commitment and differentiation of bone cells. Crit Rev Eukaryot Gene Expr. 19:1–46. 2009. View Article : Google Scholar : PubMed/NCBI
30	Anderson HC: Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol. 41:59–72. 1969. View Article : Google Scholar : PubMed/NCBI
31	Scimeca M, Giannini E, Antonacci C, Pistolese CA, Spagnoli LG and Bonanno E: Microcalcifications in breast cancer: An active phenomenon mediated by epithelial cells with mesenchymal characteristics. BMC Cancer. 14:2862014. View Article : Google Scholar : PubMed/NCBI
32	Markiewicz A, Ahrends T, Wełnicka-Jaśkiewicz M, Seroczyńska B, Skokowski J, Jaśkiewicz J, Szade J, Biernat W and Zaczek AJ: Expression of epithelial to mesenchymal transition-related markers in lymph node metastases as a surrogate for primary tumor metastatic potential in breast cancer. J Transl Med. 10:2262012. View Article : Google Scholar : PubMed/NCBI