Overexpression of the EMT Driver Brachyury in Breast Carcinomas: Association With Poor Prognosis

Palena, Claudia; Roselli, Mario; Litzinger, Mary; Ferroni, Patrizia; Costarelli, Leopoldo; Spila, Antonella; Cavaliere, F.; Huang, Bruce; Fernando, Romaine I.; Hamilton, Duane H.; Jochéms, Caroline; Tsang, Kwong Y.; Cheng, Qing; Lyerly, H. Kim; Schlom, Jeffrey; Guadagni, Fiorella

doi:10.1093/jnci/dju054

Cited by 68 publications

(92 citation statements)

References 44 publications

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“…This fact should be taken into consideration when evaluating its expression in a biopsy specimen, which would measure the level of brachyury in a specific site and at that one moment in time. In agreement with these postulates, expression of brachyury, for example, has been observed in a minority of cells in the primary tumor, while a higher proportion of brachyury-positive tumor cells and higher levels of expression have been observed in metastatic lymph nodes or distal metastases derived from the same patient (Palena, Roselli, et al, 2014).…”

Section: Poxvirus-based Brachyury Vaccinesupporting

confidence: 66%

Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines

Palena

Hamilton

2015

Advances in Cancer Research

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As a manifestation of their inherent plasticity, carcinoma cells undergo profound phenotypic changes during progression towards metastasis. One such phenotypic modulation is the epithelial-mesenchymal transition (EMT), an embryonically relevant process that can be reinstated by tumor cells, resulting in the acquisition of metastatic propensity, stem-like cell properties and resistance to a variety of anti-cancer therapies, including chemotherapy, radiation and some small molecule targeted therapies. Targeting of the EMT is emerging as a novel intervention against tumor progression. This review focuses on the potential use of cancer vaccine strategies targeting tumor cells that exhibit mesenchymal-like features, with an emphasis on the current status of development of vaccine platforms directed against the T-box transcription factor brachyury, a novel cancer target involved in tumor EMT, stemness and resistance to therapies. Also presented is a summary of potential mechanisms of resistance to immune-mediated attack driven by EMT and the development of novel combinatorial strategies based on the use of agents that alleviate tumor EMT for an optimized targeting of plastic tumor cells that are responsible for tumor recurrence and the establishment of therapeutic refractoriness.

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Section: Poxvirus-based Brachyury Vaccinesupporting

confidence: 66%

Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines

Palena

Hamilton

2015

Advances in Cancer Research

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“…Furthermore, Brachyury mRNA expression in primary lung carcinoma tissues was demonstrated as a significant predictor of poor prognosis for 5-year disease-free survival and overall survival rates and was significantly correlated to vascular invasion, lymphatic permeation, histological grade, pathologic T stage, and pathologic N stage [33]. In addition, Palena and colleagues also revealed that overexpression of brachyury in breast carcinomas is associated with poor prognosis [34]. More recently, Brachyury was shown to be overexpressed in prostate cancer and metastatic tumors when compared with normal tissues and play an important role in prostate cancer aggressiveness [35].…”

Section: Discussionmentioning

confidence: 96%

Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma

et al. 2014

J Exp Clin Cancer Res

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Aims: Brachyury overexpression has been reported in various human malignant neoplasms, but its expression and function in hepatocellular carcinoma progression and metastasis remains unknown. The present study aimed to evaluate the critical role of Brachyury in HCC metastasis. Methods: The expression of Brachyury in human HCC (SMMC7721, HepG2, FHCC98, and Hep3B) and control cell lines was analyzed using quantitative reverse-transcriptase polymerase chain reaction and immunoflourence methods. Cancerous tissues collected from patients with HCC (n = 112) were analyzed using immunohistochemical method; a microarray analysis of HCC tissues was performed to explore the clinicopathological variables of HCC. The migratory and invasive capacities of Brachyury-SMMC7721 and Brachyury-HepG2 transfected cells were evaluated using in vitro scratch wound healing and Matrigel invasion assays, respectively. Further, six-week-old male BALB/c nude mice (n = 10) model was used in vivo assay.Results: Elevated expression of Brachyury was detected in HCCs (62.5%) compared with that in adjacent nontumorous tissues. Clinicopathological analysis revealed a close correlation of Brachyury expression with distant metastasis and poor prognosis of HCC. Overexpression of Brachyury promoted epithelial-mesenchymal transition (EMT) and metastasis of HCC cells in vitro and in vivo. Brachyury overexpression enhanced Akt activation by inhibiting phosphatase and tensin homolog (PTEN), which led to subsequent stabilization of Snail, a critical EMT mediator. Conclusion:The study findings suggest that elevated Brachyury facilitates HCC metastasis by promoting EMT via PTEN/Akt/Snail-dependent pathway. Brachyury plays a pivotal role in HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target.

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“…Tumor cell mesenchymalization takes place when epithelial cancer cells lose their polarity, cell-to-cell contacts, and expression of epithelial proteins, including E-cadherin, ZO-1, and cytokeratins, while gaining the expression of proteins normally found in mesenchymal cells, such as fibronectin and vimentin (34,35). Mesenchymalization and the molecular drivers of the process, including the transcription factors Snail, Slug, Twist, and brachyury, have been linked to advanced tumor stage (36)(37)(38), presence of metastases (39), and poor prognosis in numerous cancer types (40)(41)(42). Additionally, mesenchymalization has been associated with resistance to anticancer therapies, including chemotherapy (43,44), small-molecule-targeted therapies (45,46), and to lysis by immune effector cells (47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

Dominguez¹,

McCampbell²,

David³

et al. 2017

JCI Insight

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Overexpression of the EMT Driver Brachyury in Breast Carcinomas: Association With Poor Prognosis

Abstract: The studies reported here provide the rationale for the use of a vaccine targeting brachyury for the therapy of human breast cancer, either as a monotherapy or in combination therapies.

Cited by 68 publications

References 44 publications

Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines

Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines

Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

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